Vanilloid receptor ligands and their use in treatments

ABSTRACT

Pyrimidine ethers and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

This application claims the benefit of U.S. Provisional Application No.60/543,896, filed Feb. 11, 2004, which is hereby incorporated byreference.

BACKGROUND

The vanilloid receptor 1 (VR1) is the molecular target of capsaicin, theactive ingredient in hot peppers. Julius et al. reported the molecularcloning of VR1 (Caterina et al., 1997). VR1 is a non-selective cationchannel which is activated or sensitized by a series of differentstimuli including capsaicin and resiniferatoxin (exogenous activators),heat & acid stimulation and products of lipid bilayer metabolism,anandamide (Premkumar et al., 2000, Szabo et al., 2000, Gauldie et al.,2001, Olah et al., 2001) and lipoxygenase metabolites (Hwang et al.,2000). VR1 is highly expressed in primary sensory neurons (Caterina etal., 1997) in rats, mice and humans (Onozawa et al., 2000, Mezey et al.,2000, Helliwell et al., 1998, Cortright et al., 2001). These sensoryneurons innervate many visceral organs including the dermis, bones,bladder, gastrointestinal tract and lungs; VR1 is also expressed inother neuronal and non-neuronal tissues including but not limited to,CNS nuclei, kidney, stomach and T-cells (Nozawa et al., 2001, Yiangou etal., 2001, Birder et al., 2001). Presumably expression in these variouscells and organs may contribute to their basic properties such ascellular signaling and cell division.

Prior to the molecular cloning of VR1, experimentation with capsaicinindicated the presence of a capsaicin sensitive receptor, which couldincrease the activity of sensory neurons in humans, rats and mice(Holzer, 1991; Dray, 1992, Szallasi and Blumberg 1996, 1999). Theresults of acute activation by capsaicin in humans was pain at injectionsite and in other species increased behavioral sensitivity to sensorystimuli (Szallasi and Blumberg, 1999). Capsaicin application to the skinin humans causes a painful reaction characterized not only by theperception of heat and pain at the site of administration but also by awider area of hyperalgesia and allodynia, two characteristic symptoms ofthe human condition of neuropathic pain (Holzer, 1991). Taken together,it seems likely that increased activity of VR1 plays a significant rolein the establishment and maintenance of pain conditions. Topical orintradermal injection of capsaicin has also been shown to producelocalized vasodilation and edema production (Szallasi and Blumberg 1999,Singh et al., 2001). This evidence indicates that capsaicin through it'sactivation of VR1 can regulate afferent and efferent function of sensorynerves. Sensory nerve involvement in diseases could therefore bemodified by molecules which effect the function of the vanilloidreceptor to increase or decrease the activity of sensory nerves.

VR1 gene knockout mice have been shown to have reduced sensorysensitivity to thermal and acid stimuli (Caterina et al., 2000)). Thissupports the concept that VR1 contributes not only to generation of painresponses (i.e. via thermal, acid or capsaicin stimuli) but also to themaintenance of basal activity of sensory nerves. This evidence agreeswith studies demonstrating capsaicin sensitive nerve involvement indisease. Primary sensory nerves in humans and other species can be madeinactive by continued capsaicin stimulation. This paradigm causesreceptor activation induced desensitization of the primary sensorynerve—such reduction in sensory nerve activity in vivo makes subjectsless sensitive to subsequent painful stimuli. In this regard bothcapsaicin and resinferatoxin (exogenous activators of VR1), producedesensitization and they have been used for many proof of conceptstudies in in vivo models of disease (Holzer, 1991, Dray 1992, Szallasiand Blumberg 1999).

BIBLIOGRAPHY

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Tominaga, M., Caterina, M. J., Malmberg, A. B., Rosen, T. A., Gilbert,H., Skinner, K., Raumann, B. E., Basbaum, A. I., and Julius, D., (1998).The cloned capsaicin receptor integrates multiple pain-producingstimuli. Neuron 21: 531-543. Yiangou-Y. Facer-P. Dyer-N HC. Chan-C L H.Knowles-C.

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SUMMARY

The present invention comprises a new class of compounds useful in thetreatment of diseases, such as vanilloid-receptor-mediated diseases andother maladies, such as inflammatory or neuropathic pain and diseasesinvolving sensory nerve function such as asthma, rheumatoid arthritis,osteoarthritis, inflammatory bowel disorders, urinary incontinence,migraine and psoriasis. In particular, the compounds of the inventionare useful for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, anxiety, depression, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders. Accordingly, the invention also comprises pharmaceuticalcompositions comprising the compounds, methods for the treatment ofvanilloid-receptor-mediated diseases, such as inflammatory orneuropathic pain, asthma, rheumatoid arthritis, osteoarthritis,inflammatory bowel disorders, urinary incontinence, migraine andpsoriasis diseases, using the compounds and compositions of theinvention, and intermediates and processes useful for the preparation ofthe compounds of the invention.

The compounds of the invention are represented by the following generalstructure:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³,R^(3′), R⁴ and X are defined below.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents, patent applications and other publications recitedherein are hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

One aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt or hydrate thereof, wherein:

X is N or C; wherein, when X is N,

represents single bond, and when X is C, then

represents a single or double bond;

-   -   R¹ is a saturated, partially saturated or unsaturated 5-, 6- or        7-membered ring containing 1, 2, 3 or 4 atoms selected from N, O        and S, wherein the carbon atoms of the ring are substituted by        0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3        substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,        cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹ is        phenyl substituted by 1, 2 or 3 substituents selected from        C₁₋₈alkyl, —C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),        —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);    -   R² is independently a partially saturated or unsaturated 8-, 9-,        10- or 11-membered bicyclic ring containing 1, 2, 3 or 4 atoms        selected from N, O and S, wherein the carbon atoms of the ring        are substituted by 0, 1 or 2 oxo groups and the ring is        substituted by 0, 1, 2 or 3 substituents selected from        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆        alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² is        independently a partially saturated or unsaturated 9-, 10- or        11-membered bicyclic carbocyclic ring substituted by 1, 2 or 3        substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,        cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(=)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S=0)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆        alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);    -   R³ and R^(3′) are independently, at each instance, H, methyl or        ethyl; or R³ and R^(3′) together may be combined with the carbon        atom to which they are attached to form cyclopropyl;    -   R⁴ is H or methyl;    -   R^(a) is independently, at each instance, H or R^(b); and

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl,the phenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.

One aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt thereof, wherein:

-   -   R² is independently a partially saturated or unsaturated 8-, 9-,        10- or 11-membered bicyclic ring containing 1, 2, 3 or 4 atoms        selected from N, O and S, wherein the carbon atoms of the ring        are substituted by 0, 1 or 2 oxo groups and the ring is        substituted by 0, 1, 2 or 3 substituents selected from        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆        alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² is        independently a partially saturated or unsaturated 9-, 10- or        11-membered bicyclic carbocyclic ring substituted by 1, 2 or 3        substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,        cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆        alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);    -   R⁴ is H or methyl;    -   R⁵ is independently in each instance selected from H, C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),        —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),        —OC(═O)R^(b), —OC(O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);    -   R^(a) is independently, at each instance, H or R^(b); and    -   R^(b) is independently, at each instance, phenyl, benzyl or        C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl being substituted by        0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,        C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,        —N(C₁₋₄alkyl)C₁₋₄alkyl.

Another aspect of the current invention relates to compounds having thegeneral structure:

or any pharmaceutically-acceptable salt thereof, wherein:

-   -   X is N or C; wherein, when X is N,        represents single bond, and when X is C, then        represents a single or double bond;    -   R¹ is a saturated, partially saturated or unsaturated 5-, 6- or        7-membered ring containing 1, 2, 3 or 4 atoms selected from N, O        and S, wherein the carbon atoms of the ring are substituted by        0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3        substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,        cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),        —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),        —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R¹ is        phenyl substituted by 1, 2 or 3 substituents selected from        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —C(═O)R^(b), —C(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);    -   R² is independently a partially saturated or unsaturated 8-, 9-,        10- or 11-membered bicyclic ring containing 1, 2, 3 or 4 atoms        selected from N, O and S, wherein the carbon atoms of the ring        are substituted by 0, 1 or 2 oxo groups and the ring is        substituted by 0, 1, 2 or 3 substituents selected from        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);    -   R³ and R^(3′) are independently, at each instance, H, methyl or        ethyl; or R³ and R^(3′) together may be combined with the carbon        atom to which they are attached to form cyclopropyl;    -   R⁴ is H or methyl;    -   R^(a) is independently, at each instance, H or R^(b); and    -   R^(b) is independently, at each instance, phenyl, benzyl or        C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl being substituted by        0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,        C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,        —N(C₁₋₄alkyl)C₁₋₄alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, the current invention has the general structure:

or any pharmaceutically-acceptable salt thereof, wherein:

-   -   R² is independently a partially saturated or unsaturated 8-, 9-,        10- or 11-membered bicyclic ring containing 1, 2, 3 or 4 atoms        selected from N, O and S, wherein the carbon atoms of the ring        are substituted by 0, 1 or 2 oxo groups and the ring is        substituted by 0, 1, 2 or 3 substituents selected from        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);    -   R⁴ is H or methyl;    -   R⁵ is independently in each instance selected from H, C₁₋₈alkyl,        C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),        —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),        —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),        —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),        —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆        alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a);    -   R^(a) is independently, at each instance, H or R^(b); and    -   R^(b) is independently, at each instance, phenyl, benzyl or        C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl being substituted by        0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,        C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,        —N(C₁₋₄alkyl)C₁₋₄alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, the current invention has the general structure:

or any pharmaceutically-acceptable salt thereof, wherein:

-   -   R² is independently a partially saturated or unsaturated 8-, 9-,        10- or 11-membered bicyclic ring containing 1, 2, 3 or 4 atoms        selected from N, O and S, wherein the carbon atoms of the ring        are substituted by 0, 1 or 2 oxo groups and the ring is        substituted by 0, 1, 2 or 3 substituents selected from        C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),        —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),        —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),        —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),        —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),        —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),        —S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),        —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),        —N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),        —N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),        —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a),    -   R⁴ is H or methyl;    -   R^(a) is independently, at each instance, H or R^(b); and    -   R^(b) is independently, at each instance, phenyl, benzyl or        C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl being substituted by        0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,        C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl,        —N(C₁₋₄alkyl)C₁₋₄alkyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is N and

represents a single bond.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is C and

represents a double bond.

In another embodiment, in conjunction with any one of the above andbelow embodiments, X is C and

represents a single bond.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is a saturated, partially saturated or unsaturated5-, 6- or 7-membered ring containing 1, 2, 3 or 4 atoms selected from N,O and S, wherein the carbon atoms of the ring are substituted by 0, 1 or2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is pyridinyl, furanyl, thiophenyl or pyrimidinyl,any of which is substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₈alkyl, C₁₋₄haloalkyl and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is pyridinyl, furanyl, thiophenyl or pyrimidinyl,any of which is substituted by 1, 2 or 3 substituents selected fromC₁₋₈alkyl, C₁₋₄haloalkyl and halo.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is pyridinyl, furanyl, thiophenyl or pyrimidinyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is phenyl substituted by 1, 2 or 3 substituentsselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R¹ is phenyl substituted by 1, 2 or 3 substituentsselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo and —OR^(a);

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is independently a partially saturated orunsaturated 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2, 3or 4 atoms selected from N, O and S, wherein the carbon atoms of thering are substituted by 0, 1 or 2 oxo groups and the ring is substitutedby 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl,halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is independently a partially saturated orunsaturated 9-, 10- or 11-membered bicyclic carbocyclic ring substitutedby 1, 2 or 3 substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆ alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a);

In another embodiment, in conjunction with any one of the above andbelow embodiments, R² is quinolin-8-yl, benzoxazol-4-yl,benzothiazol-4-yl or quinoxalinon-5-yl, either of which is substitutedby 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl,halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR_, —OC(═O)R^(b), —C(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆ alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a).

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ is H.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R^(3′) is methyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R³ and R^(3′) combine with the carbon atom to whichthey are attached to form cyclopropyl.

In another embodiment, in conjunction with any one of the above andbelow embodiments, R⁴ is H. In another embodiment, in conjunction withany one of the above and below embodiments, R⁴ is methyl.

Another aspect of the invention relates to a method of treating acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, anxiety, depression,inflammatory eye disorders, inflammatory or unstable bladder disorders,psoriasis, skin complaints with inflammatory components, chronicinflammatory conditions, inflammatory pain and associated hyperalgesiaand allodynia, neuropathic pain and associated hyperalgesia andallodynia, diabetic neuropathy pain, causalgia, sympatheticallymaintained pain, deafferentation syndromes, asthma, epithelial tissuedamage or dysfunction, herpes simplex, disturbances of visceral motilityat respiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound according toany of the above embodiments.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound according to any of the above embodiments and apharmaceutically-acceptable diluent or carrier.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments as a medicament.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments in the manufacture of amedicament for the treatment of acute, inflammatory and neuropathicpain, dental pain, general headache, migraine, cluster headache,mixed-vascular and non-vascular syndromes, tension headache, generalinflammation, arthritis, rheumatic diseases, osteoarthritis,inflammatory bowel disorders, anxiety, depression, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders.

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

Unless otherwise specified, the following definitions apply to termsfound in the specification and claims:

“C_(α-β)alkyl” means an alkyl group comprising a minimum of a and amaximum of β carbon atoms in a branched, cyclical or linear relationshipor any combination of the three, wherein α and β represent integers. Thealkyl groups described in this section may also contain one or twodouble or triple bonds. Examples of C₁₋₆alkyl include, but are notlimited to the following:

“Benzo group”, alone or in combination, means the divalent radicalC₄H₄═, one representation of which is —CH═CH—CH═CH—, that when vicinallyattached to another ring forms a benzene-like ring—for exampletetrahydronaphthylene, indole and the like. The terms “oxo” and “thioxo”represent the groups ═O (as in carbonyl) and ═S (as in thiocarbonyl),respectively.

“Halo” or “halogen” means a halogen atoms selected from F, Cl, Br and I.

“C_(V-W)haloalkyl” means an alkyl group, as described above, wherein anynumber—at least one—of the hydrogen atoms attached to the alkyl chainare replaced by F, Cl, Br or I.

“Heterocycle” means a ring comprising at least one carbon atom and atleast one other atom selected from N, O and S. Examples of heterocyclesthat may be found in the claims include, but are not limited to, thefollowing:

“Available nitrogen atoms” are those nitrogen atoms that are part of aheterocycle and are joined by two single bonds (e.g. piperidine),leaving an external bond available for substitution by, for example, Hor CH₃.

“Pharmaceutically-acceptable salt” means a salt prepared by conventionalmeans, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. When compounds of the invention include an acidic functionsuch as a carboxy group, then suitable pharmaceutically acceptablecation pairs for the carboxy group are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium, quaternaryammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” see infra and Berge et al., J.Pharm. Sci. 66:1 (1977).

“Saturated or unsaturated” includes substituents saturated withhydrogens, substituents completely unsaturated with hydrogens andsubstituents partially saturated with hydrogens.

“Leaving group” generally refers to groups readily displaceable by anucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

“Protecting group” generally refers to groups well known in the artwhich are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl,phthaloyl and the like. A mixture of protecting groups can be used toprotect the same amino group, such as a primary amino group can beprotected by both an aralkyl group and an aralkoxycarbonyl group. Aminoprotecting groups can also form a heterocyclic ring with the nitrogen towhich they are attached, for example, 1,2-bis(methylene)benzene,phthalimidyl, succinimidyl, maleimidyl and the like and where theseheterocyclic groups can further include adjoining aryl and cycloalkylrings. In addition, the heterocyclic groups can be mono-, di- ortri-substituted, such as nitrophthalimidyl. Amino groups may also beprotected against undesired reactions, such as oxidation, through theformation of an addition salt, such as hydrochloride, toluenesulfonicacid, trifluoroacetic acid and the like. Many of the amino protectinggroups are also suitable for protecting carboxy, hydroxy and mercaptogroups. For example, aralkyl groups. Alkyl groups are also suitablegroups for protecting hydroxy and mercapto groups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-trisilyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′═O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

The specification and claims contain listing of species using thelanguage “selected from . . . and . . . ” and “is . . . or . . . ”(sometimes referred to as Markush groups). When this language is used inthis application, unless otherwise stated it is meant to include thegroup as a whole, or any single members thereof, or any subgroupsthereof. The use of this language is merely for shorthand purposes andis not meant in any way to limit the removal of individual elements orsubgroups as needed.

EXPERIMENTAL

Unless otherwise noted, all materials were obtained from commercialsuppliers and used without further purification. All parts are by weightand temperatures are in degrees centigrade unless otherwise indicated.All microwave assisted reactions were conducted with a Smith Synthesizerfrom Personal Chemistry, Uppsala, Sweden. All compounds showed NMRspectra consistent with their assigned structures. Melting points weredetermined on a Buchi apparatus and are uncorrected. Mass spectral datawas determined by electrospray ionization technique. All examples werepurified to >90% purity as determined by high-performance liquidchromatography (HPLC). Chiral HPLC separations were conducted with aChirobiotic TAG column from Advanced Separation Technologies Inc. Unlessotherwise stated, reactions were run at room temperature.

The following abbreviations are used: DMSO dimethyl sulfoxide DMFN,N-dimethylformamide THF tetrahydrofuran Et₂O diethyl ether EtOAc ethylacetate MeOH methyl alcohol EtOH ethyl alcohol MeCN acetonitrile MeIiodomethane NMP 1-methyl-2-pyrrolidinone DCM dichloromethane TFAtrifuoroacetic acid MP-carbonate macroporous polystyrene anion-exchangeresin that is a resin bound equivalent of tetraalkylammonium carbonate.sat. saturated h hour min minutes

Example 1

(a) 4-(6-Chloro-pyrimidin-4-yloxy)-benzothiazol-2-ylamine. To a 100-mL,round-bottomed flask containing 4,6-dichloro-pyrimidine (9.0 g, 60 mmol,Aldrich) and 2-amino-benzothiazol-4-ol (5.0 g, 30 mmol, CarboGen) wasadded potassium carbonate (4.1 g, 30 mmol, Aldrich) anddimethylsulfoxide (10 mL). The reaction mixture was heated at 95° C.with stirring for 4.5 h, and at room temperature for 16 h. The resultingsolid was collected by filtration, washed with water (500 mL) anddichloromethane (500 mL), and dried in vacuo to obtain the titlecompound as a yellow solid.

(b) N-[4-(6-Chloro-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide. Amixture of 4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-ylamine,Example 1(a), (4.0 g, 14 mmol), toluene (10 mL) and acetic anhydride(4.1 mL, 43 mmol, Aldrich) was heated at 85° C. with stirring for 2 hand then stirred at room temperature for 16 h. The solvent wasevaporated under reduced pressure, and the resulting orange solid wassuspended in dichloromethane, collected by filtration and dried undervacuo to obtain the title compound as an off-white solid. M.p: 268-275°C. MS (ESI, pos. ion.) m/z: 321 (M+1).

(c)4-[6-(2-Acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester. To a mixture ofN-[4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide, Example1(b), (1.5 g, 4.7 mmol) and piperazine-1-carboxylic acid tert-butylester (1.7 g, 9.4 mmol, Fluka) was added DMF (6 mL) and potassiumcarbonate (2.6 g, 18.8 mmol). The reaction mixture was heated at 80° C.with stirring for 1 h, left to reach room temperature, and diluted withwater (100 mL). The green precipitate was filtered, washed withmethanol, and dried in vacuo to give the title compound. MS (ESI, pos.ion.) m/z: 471 (M+1).

(d)N-[4-(6-piperazin-1-yl-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide.To a suspension of4-[6-(2-acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester, Example 1 (c), (0.45 g, 0.96 mmol) indichloromethane (60 mL) was added TFA (15 mL, 195 mmol, Aldrich) withstirring at 0° C. The reaction mixture was stirred at room temperaturefor 18 h, quenched with sat. solution of NaHCO₃, and extracted withCH₂Cl₂ (2×100 mL). The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo. The solid white residue wassuspended in MeOH, filtered and dried in vacuo to give the titlecompound. M.p: 250.3-255.8° C. MS (ESI, pos. ion.) m/z: 471 (M+1).

(e)N-[4-(6-{4-[(1S,1R)-1-(2-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide.A solution of titanium(IV) isopropoxide (0.14 mL, 4.48 mmol, Aldrich),N-[4-(6-piperazin-1-yl-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide,Example 1(d), (0.06 g, 0.16 mmol), and 2′-fluoro-acetophenone (0.03 mL,0.24 mmol, Aldrich) in THF (0.6 mL) was heated at 75° C. with stirringfor 16 h. The reaction mixture was cooled to −48° C. and diluted withTHF (3 mL). Sodium borohydride (0.02 g, 0.48 mmol) was added, and thestirred reaction mixture was allowed to warm to room temperature withstirring over 5 h. To the mixture was added MeOH (2 mL) dropwise, andaqueous NaOH (1N, 50 mL). The product was extracted with ethyl acetate(2×50 mL). The combined extracts were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (gradient: 0-5% MeOH/CH₂Cl₂) to give the title compoundas a pale-yellow solid. M.p: 202.6-204.3° C. MS (ESI, pos. ion.) m/z:493.2 (M+1).

Example 2

(a) 4-[(1S,1R)-1-(4-Fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester. To a solution of piperazine-1-carboxylic acidtert-butyl ester (0.39 g, 2.2 mmol, Fluka) and 4-fluoro-acetophenone(0.39 mL, 3.3 mmol, Aldrich) in THF (2 mL) was added titanium(IV)isopropoxide (1.9 mL, 6.6 mmol, Aldrich) and the reaction mixture wasstirred at 75° C. for 18 h under nitrogen atmosphere. The mixture wascooled to −48° C., treated with NaBH(OAc)₃ (1.23 g, 6.44 mmol, Aldrich)and methanol (1 mL) and allowed to warm to room temperature over 3.5 h.The reaction mixture was diluted with EtOAc (100 mL) and washed withaqueous NaOH (1N, 3×100 mL). The organic layer was separated, dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel column chromatography (gradient: 04% MeOH/CH₂Cl₂) to give thetitle compound as a yellow oil. MS (ESI, pos. ion.) m/z: 309.2 (M+1).

(b) 1-[(1S,1R)-1-(4-Fluoro-phenyl)-ethyl]-piperazine. To a solution of4-[(1S,1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester, Example 2(a), (0.42 g, 1.36 mmol) in CH₂Cl₂ (5 mL) wasadded TFA (0.5 mL, 6.5 mmol, Aldrich) dropwise with stirring at 0° C.The reaction mixture was stirred at room temperature for 18 h andevaporated under reduced pressure. The residue was dried in vacuo togive the crude title compound, which was used in the next step withoutpurification.

(c) N-[4-(6-{4-[(1S,1R)-1-(4-Fluoro-phenyl)-ethyl]-piperazine1-yl}-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide. To a solution of1-[(1S,1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine (the cude product fromstep (b) above) in DMF (4 mL) was addedN-[4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide, Example1(b), (0.25 g, 0.76 mmol) and NaHCO₃ (0.42 g, 3.04 mmol). The reactionmixture was stirred at 85° C. for 5 h, cooled to room temperature anddiluted with water (20 mL). The mixture was extracted with CH₂Cl₂ (2×25mL) and the combined organic extracts were dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (gradient: 0-5% MeOH/CH₂Cl₂) to givethe title compound as a white amorphous solid. M.p.: 247.3° C. MS (ESI,pos. ion.) m/z: 493 (M+1).

ADDITIONAL EXAMPLES

The following examples were prepared fromN-[4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide (Example1(b)) according to the general procedure described for the preparationof Example 2, or with slight modifications thereof: M.S. (ESI) Melt.Point Ex. Structure m/z (° C.) 3

543 (M + 1) 153.4-154.5 4

555 (M + 1) 238-240 5

507 (M + 1) 231.1-232.5 6

505 (M + 1) 151 7

521 (M + 1) 218.9-219.7 8

521 (M + 1) 196.6-196.7 9

507 (M + 1) 211.6-215.8 10

507 (M + 1) 212.2-212.5 11

511 (M + 1) 256-268 12

509 (M + 1) 242-250 13

493 (M + 1) 204 14

507 (M + 1) 232-234 15

481 (M + 1) 135-140 16

481 (M + 1) 137.5-142.4 17

465 (M + 1) 138.6-139.7 18

561 (M + 1) 135-141 19

474 (M + 1) 278.1-278.5 20

515 (M + 1) 217.4-218.5

Example 21

(a) 4-[(1S)-1-(4-Fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester and4-[(1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester. The two enantiomers of4-[(1S,1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester, Example 2 (a), (1.29 g, 4.2 mmol) were separated bychiral HPLC (100% MeOH/0.08% AcOH/0.02% triethyl amine). The firstfraction was collected and concentrated in vacuo to yield4-[(1S)-1-(4-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester as a pale-yellow oil. The second fraction was collectedand concentrated in vacuo to yield4-[(1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester as a pale-yellow oil.

(b) N-[4-(6-{4-[(1S)-1-(4-Fluoro-phenyl)-ethyl]-piperazine1-yl}-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide. To a suspensionof 4-[1(S)-(4-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester, Example 21(a), (0.42 g, 1.35 mmol) in CH₂Cl₂ (2 mL)was added TFA (0.5 mL, 6.5 mmol, Aldrich) with stirring at 0° C. Thereaction mixture was stirred at room temperature for 18 h and evaporatedunder reduced pressure. The residue was dissolved in DMF (3 mL), and tothe solution was addedN-[4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide, Example1(b), (0.43 g, 1.35 mmol) and cesium carbonate (1.3 g, 4.05 mmol). Thereaction mixture was heated at 85° C. with stirring, and the progress ofthe reaction was monitored by TLC (5% MeOH/CH₂Cl₂). After completion ofthe reaction, the mixture was cooled to room temperature and dilutedwith water (40 mL). The resulting pale-yellow solid was filtered anddried in vacuo. The solid was purified by silica gel columnchromatography (gradient: 0-5% MeOH/CH₂Cl₂) to yield the title compoundas an amorphous white solid. M.p.: 243.6-245.7° C. MS (ESI, pos. ion.)m/z: 493 (M+1).

Example 22

N-[4-(6-{4-[(1R)-1-(4-Fluoro-phenyl)-ethyl]-piperazine1-yl}-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide. According to theprocedures described in Example 21(b),4-[(1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acidtert-butyl ester, Example 21(a), (0.48 g, 1.6 mmol) andN-[4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-yl]-acetamide, Example1(b), (0.512 g, 1.6 mmol) provided the title compound as a white solid.M.p.: 243.8-245.9° C. MS (ESI, pos. ion.) m/z: 493 (M+1).

Example 23

(a) 8-(6-Chloro-pyrimidin-4-yloxy)-quinolin-2-ylamine. To a 50-mL,round-bottomed flask containing 4,6-dichloropyrimidine (0.5 g, 3.4 mmol,Aldrich), 2-amino-8-hydroxyquinoline (0.54 g, 3.4 mmol, Sigma) and DMF(4 mL) was added potassium carbonate (1.9 g, 13.6 mmol). The suspensionwas stirred for 5 h under nitrogen atmosphere at 75° C. The reactionmixture was cooled to room temperature, diluted with water (50 mL), andextracted with CH₂Cl₂ (2×75 mL). The combined extracts were dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel column chromatography (gradient: 0-50% EtOAc/hexane) to givethe title compound as a white solid. M.p.: 185-186° C. MS (ESI, pos.ion.) m/z: 273 (M+1).

(b)1-[(1R)-1-(4-Fluoro-phenyl)-ethyl]-4-(toluene-4-sulfonyl)-piperazine. Amixture of N,N-bis(2-chloroethyl)-p-toluenesulfonamide (tech. 90%, 46.8g, 158 mmol, Lancaster) and (1R)-1-(4-fluorophenyl)ethylamine (20 g, 144mmol, SynQuest) in N,N-diisopropylethylamine (50 mL) was heated at 125°C. with stirring under a nitrogen atmosphere for 18 h. The reactionmixture was cooled to below 100° C. and a 7/3 mixture of EtOH/H₂O (120mL) was added slowly with stirring. The mixture was left to reach roomtemperature and the stirring was continued for 2.5 h. The solidprecipitate was filtered, and washed with H₂O (3×50 mL) and hexanes(2×50 mL). The solids were dried in vacuo at 50° C. for 18 h, andstirred in 1:1 mixture of EtOH/H₂O (140 mL) for 75 min. The solidprecipitate was filtered, washed with a 1:1 mixture of EtOH/H₂O (40 mL)and a 7:3 mixture of EtOH/H₂O (20 mL), and dried in vacuo at 50° C. for6 h to give the title compound as an off-white solid. MS (ESI, pos.ion.) m/z: 363 (M+1).

(c) 1-[(1R)-1-(4-Fluoro-phenyl)-ethyl]-piperazine. A mixture of1-[(1R)-1-(4-fluoro-phenyl)-ethyl]-4-(toluene-4-sulfonyl)-piperazine,Example 23(b), (20 g, 55 mmol), 4-hydroxybenzoic acid (22.9 g, 166 mmol,Aldrich) and HBr solution in AcOH (33 wt %, 200 mL, Aldrich) was stirredat room temperature under nitrogen atmosphere for 48 h. Water (200 mL)was added slowly and the mixture was stirred for 2 h at roomtemperature. The solid precipitate was filtered and the filter cake waswashed with H₂O (2×50 mL). The filtrate and the H₂O washes were combinedand extracted with toluene (4×50 mL). The aqueous phase was cooled in anice bath and treated portionwise with solid KOH (235 g) until pH>10. Theaqueous solution was extracted with toluene (3×50 mL) and ethyl acetate(50 mL). The combined organic extracts were washed with brine (100 mL),dried over MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was dried in vacuo to yield the title compound as a pale-brownsolid. MS (ESI, pos. ion.) m/z: 209 (M+1).

(d)8-(6-{4-[(1R)-(4-Fluoro-phenyl)-ethyl]-piperazine-1-yl}-pyrimidin-4-yloxy)-quinolin-2-ylamine.To a solution of 1-[(1R)-(4-fluoro-phenyl)-ethyl]-piperazine, Example23(c), (0.15 g, 0.72 mmol) and8-(6-chloro-pyrimidin-4-yloxy)-quinolin-2-ylamine, Example 23(a), (0.19g, 0.72 mmol) in DMF (4 mL) was added potassium carbonate (0.7 g, 2.2mmol), and the reaction mixture was heated at 85° C. with stirring undernitrogen atmosphere for 8 h. The reaction mixture was allowed to reachroom temperature and was diluted with water (20 mL). The resultingoff-white solid precipitate was filtered, and dissolved in CH₂Cl₂ (20mL). The solution was washed with water (2×50 mL), dried over Na₂SO₄,filtered, and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (gradient: 0-5%MeOH/CH₂Cl₂) and then recrystalized in EtOAc/hexane to give the titlecompound as a white solid. MS (ESI, pos. ion.) m/z: 445 (M+1).

Example 24

8-(6-{4-[(1S)-(4-Fluoro-phenyl)-ethyl]-piperazine-1-yl}-pyrimidin-4-yloxy)-quinolin-2-ylamine.1-[(1S)-(4-Fluoro-phenyl)-ethyl]-piperazine (0.15 g, 0.72 mmol, preparedfrom (1S)-1-(4-fluorophenyl)ethylamine (SynQuest) according steps (b)and (c) of Example 1023) was reacted with8-(6-chloro-pyrimidin-4-yloxy)-quinolin-2-ylamine (0.19 g, 0.72 mmol)under the conditions of Example 23(d) to give the title compound as awhite solid. M.p.: 167° C. MS (ESI, pos. ion.) m/z: 445 (M+1).

Example 25

(a) 3-Methoxy-2-nitro-phenylamine. A mixture of 2-amino-3-nitrophenol(25.0 g, 162 mmol, Aldrich) and K₂CO₃ (27 g, 195 mmol) in DMF (65 ml)was stirred at room temperature for 1 h. Methyl iodide (12.2 mL, 195mmol, Aldrich) was added and the reaction was stirred at roomtemperature for 30 h. The reaction was diluted with H₂O and extractedwith EtOAc (3×). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo. The dark-red solid wasrecrystallized from hexanes to yield the title compound as orangeneedles. MS (ESI, pos. ion) m/z: 169 (M+1).

(b) 3-Methoxy-benzene-1,2-diamine sulfate. A mixture of3-methoxy-2-nitro-phenylamine, Example 25 (a), (4.6 g, 27 mmol), ironpowder (10.7 g, 191 mmol, Aldrich), EtOH (130 mL) and H₂O (10 mL) washeated at 50° C. A solution of HCl (12.1 M, 1.7 mL) was added dropwisewith stirring. The mixture was heated at reflux for 3 h and allowed tocool to room temperature. After neutralization with NaOH and filtrationthrough Celite®, the solvent was removed in vacuo and the residue waspartitioned between CH₂Cl₂ and sat. aq. NaHCO₃. After extraction withCH₂Cl₂ (3×), the combined organic layers were concentrated. The residuewas re-dissolved in EtOH (30 mL) and treated with concentrated H₂SO₄until no more precipitate was formed. The resulting solid was removed byfiltration, washed with EtOH and dried in vacuo for 20 h at roomtemperature to give the title compound as an off-white powder. MS (ESI,pos. ion) m/z: 139 (M-HSO₄ ⁻).

(c) 3-Amino-8-methoxy-1H-quinoxalin-2-one and3-amino-5-methoxy-1H-quinoxalin-2-one. To a suspension of3-methoxy-benzene-1,2-diamine sulfate, Example 25(b), (2.36 g, 10 mmol)in EtOH (15 mL) and H₂O (1 mL) was added NaHCO₃ (1.68 g, 20 mmol, J TBaker). When gas evolution was complete, ethoxy-imino-acetic acid ethylester (1.6 g, 11 mmol, prepared according to J. Chem. Soc. Perkin.Trans. 1, 1999, 1789) was added and the mixture was stirred at roomtemperature for 16 h. The reaction was diluted with sat. aq. NaHCO₃ andextracted with 25% i-PrOH(CHCl₃ (5×). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo. Purification bysilica gel column chromatography (gradient: 0-5% MeOH/CH₂Cl₂) afforded3-amino-8-methoxy-1H-quinoxalin-2-one as a light-brown powder [MS (ESI,pos. ion) m/z: 192 (M+1)] and 3-amino-5-methoxy-1H-quinoxalin-2-one as alight-brown powder [MS (ESI, pos. ion) m/z: 192 (M+1)].

(d) 3-Amino-5-hydroxy-1H-quinoxalin-2-one. To a suspension of3-amino-5-methoxy-1H-quinoxalin-2-one, Example 25(c), (0.47 g, 2.5 mmol)in benzene (25 mL) was added AlCl₃ (0.97 g, 7.4 mmol, Aldrich) and themixture was heated to reflux with stirring for 2 h. The reaction mixturewas cooled to room temperature and quenched by the careful addition ofsatd aq. NaHCO₃. The resulting mixture was extracted with 25%i-PrOH/CHCl₃ (5×). The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuo to afford a brown powder. MS (ESI,pos. ion) m/z: 178 (M+1).

(e)4-Chloro-6-{4-[(1S,1R)-1-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-pyrimidine.1-[(1S,1R)-1-(4-Fluoro-phenyl)-ethyl]-piperazine, Example 2(b), (0.87 g,4.2 mmol) was reacted with 4,6-dichloropyrimidine (0.7 g, 4.6 mmol,Aldrich) under the conditions described in Example 1(c) to give thetitle compound as a white solid. MS (ESI, pos. ion.) m/z: 321 (M+1).

(f)3-Amino-5-(6-{4-[(1S,1R)-1-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-4-yloxy)-1H-quinoxalin-2-one.A mixture of4-chloro-6-{4-[(1S,1R)-1-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-pyrimidine,Example 25(e), (0.18 g, 0.56 mmol),3-amino-5-hydroxy-1H-quinoxalin-2-one, Example 25(d), (0.10 g, 0.56mmol) and K₂CO₃ (0.12 g, 0.85 mmol, Aldrich) in DMF (5 mL) was heated at80° C. with stirring for 24 h. After cooling to room temperature, Cs₂CO₃(0.36 g, 1.1 mmol, Aldrich) was added, and the mixture was stirred at90° C. for 96 h. The mixture was cooled to room temperature, dilutedwith H₂O and extracted with 25% i-PrOH/CHCl₃ (5×). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated in vacuo.The residue was purified by silica gel column chromatography (gradient:0-5% (2M NH₃ in MeOH)/CH₂Cl₂) to give the title compounds as a whiteamorphous powder. MS (ESI, pos. ion) m/z: 462.2 (M+1).

Example 26

(a) 3-Amino-5-(6-chloro-pyrimidin-4-ylmethyl)-1H-quinoxalin-2-one. To asolution of 4,6-dichloropyrimidine (0.30 g, 2.0 mmol, Aldrich) and3-amino-5-hydroxy-1H-quinoxalin-2-one, Example 25(d), (0.35 g, 2.0 mmol)in DMF (10 mL) was added K₂CO₃ (0.33 g, 2.4 mmol, Aldrich) and themixture was stirred at room temperature for 24 h. The reaction mixturewas diluted with H₂O and the light-brown solid precipitate was filtered.The filter cake was washed with H₂O and air-dried to give the titlecompound. MS (ESI, pos. ion) m/z: 290.1 (M+1).

(b)3-Amino-5-(6-{4-[(1R)-1-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-4-yloxy)-1H-quinoxalin-2-one.A mixture of3-amino-5-(6-chloro-pyrimidin-4-ylmethyl)-1H-quinoxalin-2-one, Example26(a), (0.17 g, 0.59 mmol) and1-[(1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine, Example 23(c), (0.12 g,0.59 mmol) was dissolved in DMF (5 mL). To the solution was added Cs₂CO₃(0.38 g, 1.2 mmol) and the mixture was heated at 85° C. with stirringfor 8 h. The reaction mixture was cooled to room temperature, dilutedwith H₂O, and the solid precipitate was filtered. The filter cake waswashed with H₂O and purified by silica gel column chromatography(gradient: 0-5% (2M NH₃ in MeOH)/CH₂Cl₂) to give the title compound asan off-white solid. Mp: 292.2-293.9° C., MS (ESI, pos. ion) m/z: 462.2(M+1).

Example 27

3-Amino-5-(6-{4-[(1S)-1-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-4-yloxy)-1H-quinoxalin-2-one.This material was prepared according to the procedure used in Example26(b) by reacting3-amino-5-(6-chloro-pyrimidin-4-ylmethyl)-1H-quinoxalin-2-one, Example26(a), (0.20 g, 0.69 mmol) with1-[(1S)-1-(4-fluoro-phenyl)-ethyl]-piperazine (0.14 g, 0.69 mmol,prepared from (1S)-1-(4-fluorophenyl)ethanamine (SynQuest) according tosteps (b) and (c) of Example 23). The title compound was isolated as anoff-white solid. Mp: 294.5-295.3° C., MS (ESI, pos. ion) m/z: 462.2(M+1).

Example 28

(a) 7-(6-Chloropyrimidin-4-yloxy)quinoline. A mixture of7-hydroxyquinoline (0.387 g, 2.67 mmol, Acros), 4,6-dichloropyrimidine(0.398 g, 2.67 mmol, Aldrich) and potassium carbonate (0.369 g, 2.67mmol, Aldrich) in DMF (3 mL) was stirred at room temperature for 16 hand then heated in a microwave synthesizer at 100° C. for 5 min. Thereaction mixture was allowed to cool to room temperature and wasfiltered. The filter cake was washed with methanol (5 mL) and thefiltrate was concentrated under reduced pressure. The reddish-brownresidue was purified by silica gel column chromatography (gradient:0-50% EtOAc/hexane) to afford the title compound as pale-yellowamorphous solid. MS (ESI, pos. ion.) m/z: 258 (M+1).

(b)7-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinoline.A solution of 7-(6-chloropyrimidin-4-yloxy)quinoline from step (a) above(0.045 g, 0.18 mmol) and 1-(1-(4-fluorophenyl)ethyl)piperazine, Example2(b), (0.036 g, 0.17 mmol,) in DMSO (0.5 mL) was heated in a microwavesynthesizer at 170° C. for 5 min. The reaction mixture was allowed tocool to room temperature and evaporated under reduced pressure. Theresidue was purified by preparative HPLC [gradient: 10-90% MeCN/(0.1%TFA in MeCN/H₂O)] to give the desired product as a TFA salt. The saltwas dissolved in DCM (25 mL) and neutralized with sat. NaHCO₃ (5 mL).The DCM layer was separated, dried over anhydrous sodium sulfate, andfiltered. The filtrate was evaporated and the residue was dried undervacuo to give the title compound as light-yellow oil. MS (ESI, pos.ion.) m/z: 430 (M+1).

Example 29

(a) 5-(6-Chloropyrimidin-4-yloxy)isoquinoline. 5-Hydroxyisoquinoline(0.431 g, 2.97 mmol, Aldrich) was reacted with 4,6-dichloropyrimidine(0.442 g, 2.97 mmol, Aldrich) under the conditions of Example 28(a) togive the title compound as pale-yellow amorphous solid. MS (ESI, pos.ion.) m/z: 258 (M+1).

(b)5-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)isoquinoline.5-(6-Chloropyrimidin-4-yloxy)isoquinoline from step (a) above (0.213 g,0.83 mmol) was reacted with 1-(1-(4-fluorophenyl)ethyl)piperazine,Example 2(b), (0.175 g, 0.84 mmol) under the conditions of Example 28(b)to give the title compound as white amorphous solid. MS (ESI, pos. ion.)m/z: 430 (M+1).

Example 30

(a) 8-(6-Chloropyrimidin-4-yloxy)quinoline. 8-Hydroxyquinoline (0.435 g,3.00 mmol, Sigma) was reacted with 4,6-dichloropyrimidine (0.449 g, 3.01mmol, Aldrich) under the conditions of Example 28(a) to give the titlecompound as pale-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 258(M+1).

(b)8-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinoline.8-(6-Chloropyrimidin-4-yloxy)quinoline from step (a) above (0.130 g,0.51 mmol) was reacted with 1-(1-(4-fluorophenyl)ethyl)piperazine,Example 2(b), (0.105 g, 0.50 mmol) under the conditions of Example 28(b)to give the title compound as off-white oil. MS (ESI, pos. ion.) m/z:430 (M+1).

Example 31

(a) 7-(6-Chloropyrimidin-4-yloxy)isoquinoline. 7-Hydroxyisoquinoline(0.286 g, 1.97 mmol, Lancaster) was reacted with 4,6-dichloropyrimidine(0.295 g, 1.98 mmol, Aldrich) under the conditions of Example 28(a) togive the title compound as pale-yellow amorphous solid. MS (ESI, pos.ion.) m/z: 258 (M+1).

-(b)7-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)isoquinoline.A mixture of 7-(6-chloropyrimidin-4-yloxy)isoquinoline from step (a)above (0.038 g, 0.15 mmol), 1-(1-(4-fluorophenyl)ethyl)piperazine,Example 2(b), (0.031 g, 0.15 mmol) and diisopropylethylamine (0.050 mL,0.29 mmol) in EtOH (0.75 mL) was heated in a microwave synthesizer at165° C. for 6 min. The reaction mixture was cooled to room temperatureand evaporated under reduced pressure. The residue was purified bypreparative HPLC [gradient: 10-90% MeCN/(0.1% TFA in MeCN/H₂O)] to givethe desired product as a TFA salt. The salt was dissolved in DCM (25 mL)and neutralized with sat. NaHCO₃ (5 mL). The DCM layer was separated,dried over anhydrous sodium sulfate, and filtered. The filtrate wasevaporated and the residue was dried under vacuo to give the titlecompound as off-white oil. MS (ESI, pos. ion.) m/z: 430 (M+1).

Example 32

(a) 3-(6-Chloropyrimidin-4-yloxy)isoquinoline. 3-Hydroxyisoquinoline(0.338 g, 2.33 mmol, Aldrich) was reacted with 4,6-dichloropyrimidine(0.348 g, 2.34 mmol, Aldrich) under the conditions of Example 28(a) togive the title compound as pale-yellow amorphous solid. MS (ESI, pos.ion.) m/z: 258 (M+1).

(b)3-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)isoquinoline.3-(6-Chloropyrimidin-4-yloxy)isoquinoline from step (a) above (0.070 g,0.27 mmol) was reacted with 1-(1-(4-fluorophenyl)ethyl)piperazine,Example 2(b), (0.057 g, 0.27 mmol) under the conditions of Example 31(b)to give the title compound as white amorphous solid. MS (ESI, pos. ion.)m/z: 430 (M+1).

Example 33

a) 4-Fluoro-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine. Toa mixture of 1-[(1S,1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine, Example2(b), (0.50 g, 2.4 mmol) and 4,6-difluoropyrimidine (0.28 mL, 2.4 mmol,ABCR) in DMF (8 mL) was added cesium carbonate (2.3 g, 7.2 mmol) withstirring at 0° C. The reaction mixture was stirred at 0° C. for 20 min,diluted with H₂O (20 mL) and extracted with DCM (2×40 mL). The combinedorganic extracts were washed with H₂O (2×40 mL), dried over Na₂SO₄ andfiltered. The filtrate was evaporated and the residue was dried in vacuoto yield the title compound. MS (ESI, pos. ion.) m/z: 305 (M+1)

b)2-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinoline.To a solution of4-fluoro-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine fromstep (a) above (0.178 g, 0.59 mmol) and quinolin-2-ol (0.085 g, 0.59mmol, Aldrich) in DMSO (2.0 mL) was added 95% sodium hydride (0.027 g,1.13 mmol, Aldrich). The mixture was stirred at room temperature for 15min and then heated in a microwave synthesizer at 170° C. for 5 min. Thereaction mixture was allowed to cool to room temperature and evaporatedunder reduced pressure. The residue was purified by preparative HPLC[gradient: 10-90% MeCN/(0.1% TFA in MeCN/H₂O)] to give the desiredproduct as a TFA salt. The salt was dissolved in DCM (25 mL) andneutralized with sat. NaHCO₃ (5 mL). The DCM layer was separated, driedover anhydrous sodium sulfate, and filtered. The filtrate was evaporatedand the residue was dried in vacuo to give the title compound asoff-white oil. MS (ESI, pos. ion.) m/z: 430 (M+1).

Example 34

(a) 4-(6-Chloropyrimidin-4-yloxy)quinoline. A mixture of4-hydroxyquinoline (0.435 g, 2.99 mmol, Aldrich), 4,6-dichloropyrimidine(0.453 g, 3.04 mmol, Aldrich) and MP-carbonate resin (0.369 g, 2.67mmol, 2.73 mmol/g, Argonaut) in NMP (2.5 mL) was stirred at roomtemperature for 2 h and then heated in a microwave synthesizer at 100°C. for 5 min. The reaction mixture was cooled to room temperature andthe resin was removed by filtration. The filter cake was washed withmethanol (10 mL) and the combined filtrate was concentrated underreduced pressure. The reddish-brown residue was purified by silica gelcolumn chromatography (gradient: 0-5% MeOH/DCM) to afford the titlecompound as pale-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 258(M+1).

(b)4-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinoline.4-(6-Chloropyrimidin-4-yloxy)quinoline from step (a) above (0.060 g,0.23 mmol) was reacted with 1-(1-(4-fluorophenyl)ethyl)piperazine,Example 2(b), (0.049 g, 0.24 mmol) under the conditions of Example 31(b)to give the title compound as off-white oil. MS (ESI, pos. ion.) m/z:430 (M+1).

Example 35

(a) 2,3-Dihydrobenzo[b][1,4]dioxin-6-yl acetate. A solution of1-(2,3-dihydrobenzo-[b][1,4]dioxin-6-yl)ethanone (1.548 g, 8.69 mmol,Aldrich) and 3-chloroperoxybenzoic acid (4.35 g, 19.41 mmol, 77% byweight, Aldrich) in DCM (55 mL) was heated to 65° C. for 17.5 h in anoil-bath. The reaction mixture was allowed to cool to room temperatureand diluted with DCM (150 mL) and water (50 mL). The DCM layer wasseparated, washed with saturated NaHCO₃ (100 mL) and brine (25 mL),dried over anhydrous sodium sulfate, and filtered. The filtrate wasevaporated and the residue was dried in vacuo to give the title compoundas an amorphous solid. MS (ESI, pos. ion.) m/z: 195 (M+1).

(b) 2,3-Dihydrobenzo[b][1,4]dioxin-6-ol. A solution of2,3-dihydrobenzo[b][1,4]dioxin-6-yl acetate from step (a) above (1.65 g,10.84 mmol, Aldrich) in MeOH (80 mL) was stirred with 2.5 N NaOH (120mL) at room temperature for 21 h. The MeOH was evaporated under reducedpressure and the residue was diluted with EtOAc (200 mL). The EtOAclayer was separated, dried over anhydrous sodium sulfate, and filtered.The filtrate was evaporated and the residue was dried under vacuo togive a reddish-brown solid. The solid was suspended in MeOH (10 mL) andfiltered. The filter cake was dried in vacuo to give the title compoundas an amorphous solid. MS (ESI, pos. ion.) m/z: 153 (M+1).

(c) 4-Chloro-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yloxy)pyrimidine. Amixture of 2,3-dihydrobenzo[b][1,4]dioxin-6-ol from step (b) above(0.500 g, 3.29 mmol), 4,6-dichloropyrimidine (0.417 g, 2.80 mmol,Aldrich) and MP-carbonate resin (1.41 g, 4.09 mmol, 2.9 mmol/g,Argonaut) in NMP (3.0 mL) was stirred at room temperature for 2 h andthen heated in a microwave synthesizer at 110° C. for 6 min. Thereaction mixture was cooled to room temperature and the resin wasremoved by filtration. The filter cake was washed with methanol (10 mL)and the filtrate was evaporated under reduced pressure. Thereddish-brown residue was purified by silica gel column chromatography(gradient: 0-5% MeOH/DCM) to afford the title compound as pale-yellowamorphous solid. MS (ESI, pos. ion.) m/z: 265 (M+1).

(d)4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yloxy)-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine.4-Chloro-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yloxy)pyrimidine from step(c) above (0.156 g, 0.59 mmol) was reacted with1-(1-(4-fluorophenyl)ethyl)piperazine, Example 2(b), (0.123 g, 0.59mmol) under the conditions of Example 31(b) to give the title compoundas off-white oil. MS (ESI, pos. ion.) m/z: 437 (M+1).

Example 36

(a) 3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl acetate.6-Acetyl-2H-benzo-[b][1,4]oxazin-3(4H)-one (1.133 g, 5.93 mmol, Aldrich)was treated with 3-chloro-peroxybenzoic acid (3.15 g, 14.06 mmol, 77% byweight, Aldrich) under the conditions of Example 35(a) to give the titlecompound as an amorphous solid. MS (ESI, pos. ion.) m/z: 208 (M+1).

(b) 6-Hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one.3-Oxo-3,4-dihydro-2H-benzo-[b][1,4]oxazin-6-yl acetate from step (a)above (1.21 g, 5.84 mmol, Aldrich) in MeOH (80 mL) was reacted with 2.5N NaOH (120 mL) under the conditions of Example 35(b) to give the titlecompound as an amorphous solid. MS (ESI, pos. ion.) m/z: 166 (M+1).

(c) 6-(6-Chloropyrimidin-4-yloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one.6-Hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one from step (b) above (0.325 g,1.97 mmol) was reacted with 4,6-dichloropyrimidine (0.264 g, 1.77 mmol,Aldrich) under the conditions of Example 35(c) to give the titlecompound as pale-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 278(M+1).

(d)6-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one.6-(6-Chloropyrimidin-4-yloxy)-2H-benzo-[b][1,4]oxazin-3(4H)-one fromstep (c) above (0.085 g, 0.31 mmol) was reacted with1-(1-(4-fluorophenyl)ethyl)piperazine, Example 2(b), (0.067 g, 0.32mmol) under the conditions of Example 31(b) to give the title compoundas off-white oil. MS (ESI, pos. ion.) m/z: 450 (M+1).

Example 37

(a) 5-(6-Chloropyrimidin-4-yloxy)quinoline. 5-Hydroxyquinoline (0.292 g,2.01 mmol, Aldrich) was reacted with 4,6-dichloropyrimidine (0.3 g, 2.01mmol, Aldrich) under the conditions of Example 34(a) to give the titlecompound as pale-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 258(M+1).

(b)5-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinoline.A mixture of 5-(6-chloropyrimidin-4-yloxy)quinoline from step (a) above(0.130 g, 0.51 mmol), 1-(1-(4-fluorophenyl)ethyl)piperazine, Example2(b), (0.107 g, 0.51 mmol) and PS-DIEA resin (0.40 g, 1.49 mmol, 3.72mmol/g, Argonaut) in EtOH (4.0 mL) was stirred at room temperature for 2h and then heated in a microwave synthesizer at 160° C. for 6 min. Thereaction mixture was allowed to cool to room temperature and the resinwas removed by filtration. The resin was washed with methanol (10 mL)and the combined filtrate was evaporated under reduced pressure. Thegummy residue was dissolved in MeOH (2.5 mL) and purified by preparativeHPLC [gradient: 10-90% MeCN/(0.1% TFA in MeCN/H₂O)]to give the desiredproduct as a TFA salt. The salt was dissolved in DCM (25 mL) andneutralized with sat. NaHCO₃ (5 mL). The DCM layer was separated, driedover anhydrous sodium sulfate, and filtered. The filtrate was evaporatedand the residue was dried in vacuo to give the title compound asoff-white oil. MS (ESI, pos. ion.) f/z: 430 (M+1).

Example 38

(a) 6-(6-Chloropyrimidin-4-yloxy)isoquinoline. 6-Hydroxyisoquinoline(0.294 g, 2.03 mmol, J & W Pharma Lab) was reacted with4,6-dichloropyrimidine (0.302 g, 2.03 mmol, Aldrich) under theconditions of Example 34(a) to give the title compound as pale-yellowamorphous solid. MS (ESI, pos. ion.) m/z: 258 (M+1).

(b)6-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)isoquinoline.6-(6-Chloropyrimidin-4-yloxy)isoquinoline from step (a) above (0.136 g,0.53 mmol) was reacted with 1-(1-(4-fluorophenyl)ethyl)piperazineExample 2(b), (0.112 g, 0.54 mmol) under the conditions of Example37(b). The crude product was purified by preparative HPLC [gradient10-90% MeCN (0.1% TFA)/H₂O (0.1% TFA)] to give the title compound asoff-white oil. MS (ESI, pos. ion.) m/z: 430 (M+1).

Example 39

(a) 6-(6-Chloropyrimidin-4-yloxy)-3,4-dihydro-2H-benzo[b] [1,4]oxazine.3,4-Dihydro-2H-benzo[b][1,4]oxazin-6-ol (0.152 g, 1.01 mmol, Matrix) wasreacted with 4,6-dichloropyrimidine (0.15 g, 1.01 mmol, Aldrich) underthe conditions of Example 34(a) to give the title compound aspale-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 264 (M+1).

(b)6-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine.6-(6-Chloropyrimidin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine fromstep (a) above (0.043 g, 0.17 mmol) was reacted with1-(1-(4-fluorophenyl)ethyl)piperazine, Example 2(b), (0.040 g, 0.19mmol) under the conditions of Example 31(b) to give the title compoundas amorphous white solid. MS (ESI, pos. ion.) m/z: 436 (M+1).

Example 40

(a) 4-(6-Chloropyrimidin-4-yloxy)isoquinoline. Isoquinolin-4-ol (0.436g, 3.00 mmol, Monomer Chem) was reacted with 4,6-dichloropyrimidine(0.449 g, 3.01 mmol, Aldrich) under the conditions of Example 34(a) togive the title compound as pale-yellow amorphous solid. MS (ESI, pos.ion.) m/z: 258 (M+1).

(b)4-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)isoquinoline.4-(6-Chloropyrimidin-4-yloxy)isoquinoline from step (a) above (0.162 g,0.63 mmol) was reacted with 1-(1-(4-fluorophenyl)ethyl)piperazine,Example 2(b), (0.135 g, 0.65 mmol) under the conditions of Example 31(b) to give the title compound as amorphous white solid. MS (ESI, pos.ion.) m/z: 430 (M+1).

Example 41

(a) 2,3-Dihydrobenzo[b][1,4]dioxin-5-ol. A mixture ofbenzene-1,2,3-triol (4.39 g, 34.81 mmol, Aldrich), 1,2-dibromoethane (1mL, 11.6 mmol, Aldrich) and potassium carbonate (1.60 g, 11.58 mmol,Aldrich) in 2-butanone (300 mL, Aldrich) was heated to reflux for 18.5 hwith stirring in an oil-bath. The reaction mixture was cooled to roomtemperature and diluted with DCM (100 mL) and water (50 mL). The DCMlayer was separated, washed with 10% aqueous Na₂S₂O₃ (50 mL) and brine(100 mL), dried over anhydrous sodium sulfate, filtered, and evaporated.The residue was purified by silica gel column chromatography (gradient:0-5% MeOH/DCM) to give the title compound as an amorphous solid. MS(ESI, pos. ion.) m/z: 153 (M+1).

(b) 4-Chloro-6-(2,3-dihydrobenzo[b][1,4]dioxin-5-yloxy)pyrimidine.2,3-Dihydro-benzo[b][1,4]dioxin-5-ol from step (a) above (0.247 g, 1.62mmol) was reacted with 4,6-dichloropyrimidine (0.232 g, 1.56 mmol,Aldrich) under the conditions of Example 34(a) to give the titlecompound as pale-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 265(M+1).

(c)4-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yloxy)-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine.4-Chloro-6-(2,3-dihydrobenzo[b][1,4]dioxin-5-yloxy)pyrimidine from step(b) above (0.234 g, 0.88 mmol) was reacted with1-(1-(4-fluorophenyl)ethyl)piperazine, Example 2(b), (0.185 g, 0.89mmol) under the conditions of Example 31(b) to give the title compoundas amorphous white solid. MS (ESI, pos. ion.) m/z: 437 (M+1).

Example 42

(a) 6-(6-Chloropyrimidin-4-yloxy)quinoline 6-Hydroxyquinoline (0.432 g,2.98 mmol, Aldrich) was reacted with 4,6-dichloropyrimidine (0.445 g,2.99 mmol, Aldrich) under the conditions of Example 28(a) to give thetitle compound as pale-yellow amorphous solid. MS (ESI, pos. ion.) m/z:258 (M+1).

(b)6-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinoline.6-(6-Chloropyrimidin-4-yloxy)quinoline from step (a) above (0.135 g,0.52 mmol) was reacted with 1-(1-(4-fluorophenyl)ethyl)piperazine,Example 2(b), (0.109 g, 0.52 mmol) under the conditions of Example 28(b)to give the title compound as white amorphous solid. MS (ESI, pos. ion.)m/z: 430 (M+1).

Example 43

(a) 5-(6-Chloropyrimidin-4-yloxy)-3,4-dihydroisoquinolin-1 (2H)-one.5-Hydroxy-3,4-dihydroisoquinolin-1(2H)-one (0.274 g, 1.68 mmol,Chempacific) was reacted with 4,6-dichloropyrimidine (0.251 g, 1.69mmol, Aldrich) under the conditions of Example 34(a) to give the titlecompound as pale-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 276(M+1).

(b)5-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-3,4-dihydroisoquinolin-1(2H)-one.5-(6-Chloropyrimidin-4-yloxy)-3,4-dihydroisoquinolin-1(2H)-one from step(a) above (0.214 g, 0.78 mmol) was reacted with1-(1-(4-fluorophenyl)ethyl)piperazine, Example 2(b), (0.162 g, 0.78mmol) under the conditions of Example 37(b) to give the title compoundas off-white oil. MS (ESI, pos. ion.) m/z: 448 (M+1).

Example 44

(a) 4-Hydroxy-1H-benzo[d]imidazol-2(3H)-one. To a suspension of2,3-diaminophenol (1.24 g, 10 mmol, Aldrich) in THF (25 mL) was addedcarbonyldiimidazole (1.62 g, 10 mmol, Aldrich). The reaction mixture wasstirred at room temperature for 16 h and evaporated in vacuo. The oilyresidue was suspended in MeOH and the solid precipitate was filtered.The filter cake was dried in vacuo to give the title compound. MS (ESI,pos. ion.) m/z: 151 (M+1).

(b) 4-(6-Chloropyrimidin-4-yloxy)-1H-benzo[d]imidazol-2(3H)-one.4-Hydroxy-1H-benzo[d]imidazol-2(3H)-one from step (a) above (150 mg, 1mmol) was reacted with 4,6-dichloropyrimidine (149 mg, 1 mmol, Aldrich)under the conditions of Example 34(a) to give the title compound. MS(ESI, pos. ion.) m/z: 263 (M+1).

(c)4-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-1H-benzo-[d]imidazol-2(3H)-one.4-(6-Chloropyrimidin-4-yloxy)-1H-benzo[d]imidazol-2(3H)-one from step(b) above (45 mg, 0.17 mmol) was reacted with1-(1-(4-fluorophenyl)ethyl)piperazine, Example 2(b), (42 mg, 0.2 mmol)under the conditions of Example 28(b) to give the title compound as awhite amorphous solid. MS (ESI, pos. ion.) m/z: 435.2 (M+1).

Example 45

(a) 2-Methyl-1H-benzo[d]imidazol-4-ol. A mixture of 2,3-diaminophenol(620 mg, 5 mmol, Aldrich) and glacial acetic acid (5 mL) was heated in amicrowave synthesizer at 200° C. for 5 min. The reaction mixture wascooled to room temperature and evaporated in vacuo to give the titlecompound as a black oil. MS (ESI, pos. ion.) m/z: 149.2 (M+1).

(b) 4-(6-Chloropyrimidin-4-yloxy)-2-methyl-1H-benzo[d]imidazole.2-Methyl-1H-benzo[d]imidazol-4-ol from step (a) above (148 mg, 1 mmol)was reacted with 4,6-dichloropyrimidine (148 mg, 1 mmol, Aldrich) underthe conditions of Example 34(a) to give the title compound as a yellowamorphous solid. MS (ESI, pos. ion.) m/z: 261 (M+1).

(c)4-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-2-methyl-1H-benzo[d]imidazole.4-(6-Chloropyrimidin-4-yloxy)-2-methyl-1H-benzo[d]imidazole from step(b) above (30 mg, 0.12 mmol) was reacted with1-(1-(4-fluorophenyl)ethyl)piperazine, Example 2(b), (0.15 mmol) underthe conditions of Example 37(b) to give the title compound as an oil. MS(ESI, pos. ion.) m/z: 433.2 (M+1).

Example 46

(a) 7-(6-Chloropyrimidin-4-yloxy)-1H-indole. 7-Hydroxyindole (400 mg, 3mmol, Synchem) was reacted with 4,6-dichloropyrimidine (450 mg, 3 mmol,Aldrich) under the conditions of Example 34(a) to give the titlecompound as a white solid. MS (ESI, pos. ion.) m/z: 246.1 (M+1).

(b)7-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-1H-indole.7-(6-Chloropyrimidin-4-yloxy)-1H-indole from step (a) above (95 mg, 0.39mmol) was reacted with 1-(1-(4-fluorophenyl)ethyl)piperazine, Example2(b), (85 mg, 0.4 mmol) under the conditions of Example 37(b) to givethe title compound as a colorless solid. MS (ESI, pos. ion.) m/z: 418.2(M+1).

Example 47

(a) 6-(6-Chloropyrimidin-4-yloxy)-1H-indole. 6-Hydroxyindole (266 mg, 2mmol, Peakdale) was reacted with 4,6-dichloropyrimidine (298 mg, 2 mmol,Aldrich) under the conditions of Example 28(a) to give the titlecompound as a colorless oil. MS (ESI, pos. ion.) m/z: 246.2 (M+1).

(b)5-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-1H-indole.6-(6-Chloropyrimidin-4-yloxy)-1H-indole from step (a) above (123 mg, 0.5mmol) was reacted with 1-(1-(4-fluorophenyl)ethyl)piperazine, Example2(b), (104 mg, 0.5 mmol) under the conditions of Example 28(b) to givethe title compound as an off white solid. MS (ESI, pos. ion.) m/z: 418(M+1).

Example 48

(a) 8-(6-Chloropyrimidin-4-yloxy)H-imidazo[1,2-a]pyridine.Imidazo[1,2-a]pyridin-8-ol (67 mg, 0.5 mmol, prepared as described in WO2004/014871) was reacted with 4,6-dichloropyrimidine (75 mg, 0.5 mmol,Aldrich) under the conditions of Example 34(a) to give the titlecompound as a colorless film. MS (ESI, pos. ion.) m/z: 247 (M+1).

(b)8-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)H-imidazo[1,2-a]pyridine.8-(6-Chloropyrimidin-4-yloxy)H-imidazo[1,2-a]pyridine from step (a)above (25 mg, 0.1 mmol) was reacted with1-(1-(4-fluorophenyl)ethyl)piperazine, Example 2(b), (25 mg, 0.12 mmol)under the conditions of Example 37(b) to give the title compound as ayellow film. MS (ESI, pos. ion.) m/z: 419.3 (M+1).

Example 49

(a) 4-(6-Chloropyrimidin-4-yloxy)-1H-indole. 4-Hydroxyindole (133 mg, 1mmol, Aldrich) was reacted with 4,6-dichloropyrimidine (185 mg, 1.25mmol, Aldrich) under the conditions of Example 34(a) to give the titlecompound as a yellow solid. MS (ESI, pos. ion.) m/z: 246 (M+1).

(b)4-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-1H-indole.4-(6-Chloropyrimidin-4-yloxy)-1H-indole from step (a) above (200 mg, 0.8mmol) was reacted with 1-(1-(4-fluorophenyl)ethyl)piperazine, Example2(b), (167 mg, 0.8 mmol) under the conditions of Example 28(b) to give105 mg (32%) of the title compound as a white amorphous solid. MS (ESI,pos. ion.) m/z: 418.2 (M+1).

Example 50

(a) 5-Hydroxy-1H-benzo[d]imidazol-2(3H)-one. To5-methoxy-1H-benzo[d]imidazol-2(3H)-one (164 mg, 1 mmol, Lancaster) inDCM (2 mL) was added 1 M solution of aluminium trichloride innitrobenzene (1 mL, 1 mmol, Aldrich). The reaction mixture was stirredat room temperature for 4 days and evaporated in vacuo. The residue wasfiltered through Celite®, and the filter cake was washed with DCM. TheDCM washings were discarded and the filter cake was washed with MeOH.The dark brown MeOH washings were collected and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(gradient: 5-20% MeOH/CH₂Cl₂) to give the title compound as apale-yellow solid. MS (ESI, pos. ion.) m/z: 151 (M+1).

(b) 5-(6-Chloropyrimidin-4-yloxy)-1H-benzo[d]imidazol-2(3H)-one.5-Hydroxy-1H-benzo[d]imidazol-2(3H)-one from step (a) above (100 mg,0.66 mmol) was reacted with 4,6-dichloropyrimidine (105 mg, 0.7 mmol,Aldrich) under the conditions of Example 34(a) to give the titlecompound as a film. MS (ESI, pos. ion.) m/z: 263 (M+1).

(c)5-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-1H-benzo[d]imidazol-2(3H)-one.5-(6-Chloropyrimidin-4-yloxy)-1H-benzo[d]imidazol-2(3H)-one from step(b) above (95 mg, 0.37 mmol) was reacted with1-(1-(4-fluorophenyl)ethyl)piperazine, Example 2(b), (80 mg, 0.38 mmol)under the conditions of Example 28(b) to give the title compound as apale-yellow amorphous solid. MS (ESI, pos. ion.) m/z: 435.2 (M+1).

Example 51

(a) 5-(6-Chloropyrimidin-4-yloxy)-3,3-dimethylindolin-2-one.5-Hydroxy-3,3-dimethylindolin-2-one (177 mg, 1 mmol, RinTech) wasreacted with 4,6-dichloro-pyrimidine (149 mg, 1 mmol, Aldrich) under theconditions of Example 34(a) to give the title compound as an oil. MS(ESI, pos. ion.) m/z: 290 (M+1).

(b)5-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-3,3-di-methylindolin-2-one.5-(6-Chloropyrimidin-4-yloxy)-3,3-dimethylindolin-2-one from step (a)above (56 mg, 0.2 mmol) was reacted with1-(1-(4-fluorophenyl)-ethyl)piperazine, Example 2(b), (40 mg, 0.19 mmol)under the conditions of Example 28(b) to give the title compound as acolorless solid. MS (ESI, pos. ion.) m/z: 462.2 (M+1).

Example 52

(a) 4-(6-Chloropyrimidin-4-yloxy)benzo[d]thiazol-2-amine.2-Aminobenzo[d]thiazol-4-ol (166 mg, 1 mmol, Carbogen) was reacted with4,6-dichloropyrimidine, (150 mg, 1 mmol, Aldrich) under the conditionsof Example 34(a) to give the title compound as a white solid. MS (ESI,pos. ion.) m/z: 279 (M+1).

(b)4-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-amine.4-(6-Chloropyrimidin-4-yloxy)benzo[d]thiazol-2-amine from step (a) above(150 mg, 0.54 mmol) was reacted with1-(1-(4-fluorophenyl)ethyl)piperazine, Example 2(b), (115 mg, 0.55 mmol)under the conditions of Example 28(b) to give the title compound as anamorphous solid. MS (ESI, pos. ion.) m/z: 451.2 (M+1).

Example 53

(a) 2-Hydroxy-6-(2-methoxy-2-oxoethyl)benzoic acid. To a solution of3-hydroxy-homophthalic acid (4.5 g, 23 mmol, Apin) in MeOH (100 mL) wasadded dropwise acetyl chloride (10 mL, 9.1 g, 115 mmol, Aldrich) withstirring at 0° C. The reaction mixture was stirred at room temperaturefor 18 h and the solvent was evaporated under reduced pressure to affordthe title compound as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm:3.57 (s, 3H), 3.84 (s, 2H), 6.78 (d, J=7.43 Hz, 1H), 6.86 (d, J=8.22 Hz,1H), 7.32 (t, J=7.82 Hz, 1H).

(b) 8-Hydroxy-1H-isochromen-3(4H)-one. To a solution of2-hydroxy-6-(2-methoxy-2-oxoethyl)benzoic acid from step (a) above (4.2g, 20 mmol) in anhydrous THF (10 mL) was added dropwise a solution ofborane-methyl sulfide complex in THF (25 mL, 50 mmol, 2.0 M, Aldrich)with stirring at room temperature under N₂ atmosphere. The reactionmixture was stirred at reflux for 3.5 h, allowed to cool to 25° C., andquenched by the slow addition of 5 N HCl (20 mL). Upon completeaddition, the mixture was stirred at reflux for 10 min and allowed tocool to 25° C. The mixture was concentrated in vacuo to a volume of 50mL, diluted with water (200 mL), and extracted with EtOAc (2×200 mL).The combined organic extract was washed with sat. NaCl (100 mL), driedover Na₂SO₄, filtered, and concentrated in vacuo to afford a whitesolid. The solid was purified by silica gel chromatography (gradient:15-50% EtOAc in hexane) to provide the title product as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm: 3.52 (s, 2H), 5.11 (s, 2H), 6.54 (d,J=7.43 Hz, 1H), 6.57 (d, J=8.22 Hz, 1H), 6.94 (t, J=7.63 Hz, 1H), 9.72(s, 1H).

(c) 8-Hydroxy-1,2-dihydroisoquinolin-3(4H)-one. [analogous to the methodof White, E. H.; Roswell, D. F.; Politzer, I. R.; Branchini, B. R.Active Site-Directed Inhibition with Substrates Producing CarboniumIons: Chymotrypsin. Methods Enzym, 1977 (46), 216-220]. A mixture of8-hydroxy-1H-isochromen-3(4H)-one from step (b) above (1.0 g, 6.1 mmol)and urea (2.2 g, 37 mmol, Aldrich) was heated at 200° C. in an oil bathwith stirring for 30 min. The reaction mixture was allowed to cool to25° C., treated with 1 N HCl (50 mL) and DCM (50 mL), and stirred for 5h to provide a suspension. The suspension was filtered and the filtercake was washed with 1 N HCl (50 mL), water (50 mL), and DCM (50 mL).The combined DCM wash and filtrate was washed with sat. NaCl (30 mL) andevaporated under reduced pressure. The residue was dried in vacuo toafford the title product as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δppm: 3.36 (s, 2H), 4.23 (s, 2H), 6.61 (d, J=7.43 Hz, 1H), 6.68 (d,J=7.82 Hz, 1H), 7.03 (t, J=7.83 Hz, 1H), 7.92 (s, 1H), 9.66 (s, 1H).

(d)(S)-8-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-1,2-dihydroisoquinolin-3(4H)-onehydrochloride. A solution of 8-hydroxy-1,2-dihydroisoquinolin-3(4H)-onefrom step (c) above (200 mg, 1.2 mmol) in anhydrous DMF (5 mL) waspurged with N₂ and treated with granular K₂CO₃ (1 g, 7.2 mmol, Aldrich)and 4,6-difluoropyrimidine (140 mg, 1.2 mmol, ABCR). The reactionmixture was magnetically stirred at 25° C. for 1 h.1-[(1-S)-1-(4-Fluoro-phenyl)-ethyl]-piperazine, (200 mg, 0.96 mmol,prepared as described in Example 27) was added and the mixture washeated at 50° C. with stirring for 30 min. The reaction mixture was leftto reach room temperature and was diluted with EtOAc (100 mL). The EtOAcsolution was decanted from the solid K₂CO₃, washed with sat. NaHCO₃ (50mL), water (50 mL), sat. NaCl (50 mL), dried over Na₂SO₄ and filtered.The filtrate was evaporated in vacuo and the residue was purified bysilica gel column chromatography (gradient: 1-10% MeOH/EtOAc) to providethe pure product as a solid. The solid was dissolved in EtOAc (50 mL)and MeOH (5 mL) and treated with 1 N HCl in Et₂O (20 mL, Aldrich). Themixture was evaporated under reduced pressure and the residue was driedin vacuo to afford the title compound as a pale-yellow amorphous solid.MS (ESI, pos. ion.) m/z: 448 (M+1). Anal. Calcd for C₂₅H₂₆N₅FO₂.1.8HCl.0.8H₂O: C, 56.92; H, 5.62; N, 13.28; Cl, 12.10; F, 3.60. Found: C,56.60; H, 5.80; N, 12.91; Cl, 12.00; F, 3.51.

Example 54

(a) 3-Methoxybenzene-1,2-diamine dihydrochloride. A mixture of3-methoxy-2-nitro-phenylamine, Example 25 (a), (18.0 g, 107 mmol),palladium on carbon (10 wt %, 1.8 g, 1.7 mmol, Aldrich) and MeOH (130mL) was stirred under H₂ atmosphere for 40 h. The mixture was filteredthrough Celite® and the filtrate was concentrated in vacuo. The residuewas dissolved in Et₂O and treated with 1M HCl in Et₂O (230 mL, 230 mmol,Aldrich). The solids were collected by filtration and washed with Et₂O.The filter cake was separated and dried in vacuo to give the titlecompound as a light-pink powder. MS (ESI, pos. ion.) t/z: 139 (M−HCl₂⁻).

(b) 8-Methoxy-1H-quinoxalin-2-one and 5-Methoxy-1H-quinoxalin-2-one. Asolution of 3-methoxybenzene-1,2-diamine dihydrochloride from step (a)above (5.28 g, 25 mmol) in EtOH (30 mL) and H₂O (70 mL) was neutralizedby careful addition of solid NaHCO₃. A solution of ethyl glyoxylate (50%in toluene, 5.45 mL, 27.5 mmol, Fluka) was added and the mixture wasstirred at room temperature for 24 h. The mixture was diluted with sataq. NH₄Cl and extracted with 25% i-PrOH/CHCl₃ (4×). The combined organicextracts were dried over Na₂SO₄, filtered and evaporated in vacuo.Purification of the residue by column chromatography (gradient: 0-2.5%2M NH₃ in MeOH/CH₂Cl₂) afforded 8-methoxy-1H-quinoxalin-2-one as anoff-white powder [MS (ESI, pos. ion) m/z: 177 (M+1)] and5-methoxy-1H-quinoxalin-2-one as an off-white powder [MS (ESI, pos.ion.) m/z: 177 (M+1)].

(c) 2-Chloro-8-methoxy-quinoxaline. A mixture of8-methoxy-1H-quinoxalin-2-one from step (b) above (5.34 g, 30.3 mmol)and POCl₃ (100 mL, 1073 mmol, Aldrich) was heated to 105° C. for 4 h.The reaction mixture was allowed to cool to room temperature evaporatedin vacuo. The residue was partitioned between sat. aq. NaHCO₃ and CH₂Cl₂and stirred for 3 h. The CH₂Cl₂ layer was separated and the aqueousphase was extracted with CH₂Cl₂ (3×). The CH₂Cl₂ extracts were combined,dried over Na₂SO₄, and filtered through a pad of silica gel. The filtercake was washed with EtOAc and the filtrates were combined. Evaporationof the solvents gave a solid residue, which was dried in vacuo to affordthe title compound. MS (ESI, pos. ion.) m/z: 195 (M+1).

(d) 8-Methoxy-quinoxalin-2-ylamine. A mixture of2-chloro-8-methoxy-quinoxaline from step (c) above (5.75 g, 29.5 mmol),conc NH₄OH (30 mL, Baker) and EtOH (3 mL) was heated to 110° C. in apressure vessel for 28 h. The reaction mixture was cooled to roomtemperature and diluted with H₂O. The solid precipitate was filtered andwashed with H₂O. The filter cake was purified on a short silica gelcolumn, eluting with 1% MeOH/CH₂Cl₂ (500 mL) and 10% MeOH/CH₂Cl₂ (500mL). The second fraction was separated and evaporated in vacuo. Thesolid residue was recrystallized from MeOH to give the title compound.MS (ESI, pos. ion.) m/z: 176 (M+1).

(e) 3-Amino-quinoxalin-5-ol. A mixture of 8-methoxy-quinoxalin-2-ylaminefrom step (d) above (2.51 g, 14.3 mmol) in CH₂Cl₂ (150 mL) was treatedwith BBr₃ (4.05 mL, 43 mmol, Aldrich) and heated to 44° C. for 6 d. Themixture was allowed to cool to room temperature, quenched with sat aq.NaHCO₃ and extracted with 25% i-PrOH/CHCl₃ (5×).

The combined organic extracts were dried over Na₂SO₄, filtered andevaporated. The residue was dried in vacuo to give the title compound.MS (ESI, pos. ion.) m/z: 162 (M+1).

(f) 8-(6-Chloropyrimidin-4-yloxy)quinoxalin-2-amine.3-Amino-quinoxalin-5-ol from step (e) above (500 mg, 3.1 mmol) wasreacted with 4,6-dichloropyrimidine (462 mg, 3.1 -mmol, Aldrich) underthe conditions of Example 26(a) to give the title compound. MS (ESI,pos. ion.) m/z: 274 (M+1).

(g)(S)-8-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinoxalin-2-amine.8-(6-Chloropyrimidin-4-yloxy)quinoxalin-2-amine from step (f) above (424mg, 1.55 mmol) was reacted with(S)-1-(1-(4-fluorophenyl)ethyl)piperazine (323 mg, 1.55 mmol, preparedas described in Example 27) under the conditions of Example 26(b) togive the title compound. MS (ESI, pos. ion.) m/z: 446 (M+1). Mp: 114° C.

Example 55

(R)-8-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinoxalin-2-amine.8-(6-Chloropyrimidin-4-yloxy)quinoxalin-2-amine, Example 54(f), (424 mg,1.55 mmol) was reacted with(R^(a))-1-(1-(4-fluorophenyl)ethyl)piperazine, Example 23(c), (323 mg,1.55 mmol) under the conditions of Example 26(b) to give the titlecompound. MS (ESI, pos. ion.) m/z: 446 (M+1). Mp: 118° C.

Example 56

(a) 5-Methoxyquinoxaline-2,3(1H,4H)-dione. 3-Methoxybenzene-1,2-diaminedihydrochloride (Example 54(a)) was partitioned between 10% aq. Na₂CO₃and CH₂Cl₂. The aqueous layer was extracted with CH₂Cl₂ (2×). Thecombined organic extracts were dried over Na₂SO₄, filtered andevaporated to yield 3-methoxybenzene-1,2-diamine. A mixture of thediamine (912 mg, 6.6 mmol) and diethyl oxalate (9.0 mL, 66 mmol,Aldrich) was heated at 185° C. for 18 h. The reaction mixture was leftto reach room temperature and the solid precipitate was filtered. Thefilter cake was washed with EtOH and dried in vacuo to give the titlecompound. MS (ESI, pos. ion.) m/z: 191 (M+1).

(b) 5-Hydroxyquinoxaline-2,3(1H,4H)-dione. To a solution of5-methoxyquinoxaline-2,3(1H,4H)-dione from step (a) above (180 mg, 0.94mg) in CH₂Cl₂ (10 mL) was added BBr₃ (1.0 M in CH₂Cl₂, 2.8 mL, 2.8 mmol,Aldrich) and the mixture was heated at 45° C. for 20 h. The reactionmixture was left to reach room temperature and the solid precipitate wasfiltered. The filter cake was washed with MeOH (3×) and dried in vacuoto give the title compound. MS (ESI, pos. ion.) m/z: 179 (M+1).

(c) 5-(6-Chloropyrimidin-4-yloxy)quinoxaline-2,3(1H,4H)-dione.5-Hydroxy-quinoxaline-2,3(1H,4H)-dione from step (b) above (356 mg, 2.0mmol) was reacted with 4,6-dichloropyrimidine (289 mg, 2.0 mmol,Aldrich) under the conditions of Example 26(a) to give the titlecompound.

(d)(R)-5-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinoxaline-2,3(1H,4H)-dione.5-(6-Chloropyrimidin-4-yloxy)quinoxaline-2,3(1H,4H)-dione from step (c)above (100 mg, 0.34 mmol) was reacted with(R^(a))-1-(1-(4-fluorophenyl)ethyl)piperazine, Example 23(c), (72 mg,0.34 mmol) under the conditions of Example 26(b) to give the titlecompound. MS (ESI, pos. ion.) t/z: 463 (M+1).

Example 57

(a) 3,5-Difluoro-2-nitrophenol. To a solution of1,3,5-trifluoro-2-nitrobenzene (10 g, 5.6 mmol, Aldrich) in DMSO (50 mL)was added 10 N NaOH (12 mL, 120 mmol, J T Baker) and the mixture wasstirred at room temperature for 20 h. The reaction mixture was dilutedwith H₂O and extracted with Et₂O. The aqueous layer was separated,acidified with conc. HCl to pH 5, and extracted with Et₂O (2×). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (gradiend: 0-30% EtOAc/hexanes) to give thetitle compound. MS (ESI, neg. ion.) m/z: 174 (M−1).

(b) 1,5-Difluoro-3-methoxy-2-nitrobenzene. To a mixture of3,5-difluoro-2-nitrophenol from step (a) above (7.18 g, 41.1 mmol) andK₂CO₃ (8.52 g, 61.7 mmol, Aldrich) in DMF (30 mL) was added iodomethane(4.36 ml, 70 mmol, Aldrich). After stirring for 18 h at roomtemperature, the mixture was diluted with H₂O and extracted with Et₂O(2×). The combined organics were dried over Na₂SO₄, filtered andevaporated under reduced pressure. The residue was dried in vacuo togive the title compound.

(c) N-(2,4-Dimethoxybenzyl)-5-fluoro-3-methoxy-2-nitrobenzenamine. Amixture of 1,5-difluoro-3-methoxy-2-nitrobenzene from step (b) above(4.00 g, 21.2 mmol), 2,4-dimethoxybenzylamine (3.18 mL, 21.2 mmol,Aldrich) and triethylamine (2.96 ml, 21.2 mmol) in THF (210 mL) washeated at 70° C. for 20 h. The reaction mixture was cooled to roomtemperature and the volatiles were removed in vacuo. The residue wasdissolved in CH₂Cl₂ and passed through a pad of silica gel, eluting withCH₂Cl₂. The CH₂Cl₂ solution was evaporated under reduced pressure andthe residue was dried in vacuo to give the title compound as a yellowsolid. MS (ESI, pos. ion.) m/z: 359 (M+23).

(d) N¹-(2,4-Dimethoxybenzyl)-5-fluoro-3-methoxybenzene-1,2-diamine. Amixture of N-(2,4-dimethoxybenzyl)-5-fluoro-3-methoxy-2-nitrobenzenaminefrom step (c) above (5.40 g, 16.1 mmol), iron powder (325 mesh, 4.32 g,77.3 mmol, Aldrich), NH₄Cl (1.19 g, 22.5 mmol, Aldrich) and conc. HCl (4drops) in EtOH (100 mL) and H₂O (20 mL) was heated to 70° C. withstirring for 3 h. The reaction mixture was left to reach roomtemperature and the stirring was continued for 16 h. The mixture wasfiltered through a Celite® pad and the filtrate was evaporated underreduced pressure. The residue was dried in vacuo to give the titlecompound.

(e)1-(2,4-Dimethoxybenzyl)-3-amino-7-fluoro-5-methoxyquinoxalin-2(1H)-one.A mixture ofN¹-(2,4-dimethoxybenzyl)-5-fluoro-3-methoxybenzene-1,2-diamine from step(d) above (4.92 g, 16.1 mmol) and ethyl 2-ethoxy-2-iminoacetate (5.54 g,38.14 mmol, prepared according to J. Chem. Soc. Perkin. Trans. 1, 1999,1789) in EtOH (100 mL) was stirred at room temperature for 18 h. Thereaction mixture was filtered and the filter cake was washed with EtOH,and dried in vacuo to give the title compound as a fine white powder. MS(ESI, pos. ion.) m/z: 360 (M+1).

(f) 3-Amino-7-fluoro-5-methoxyquinoxalin-2(1H)-one. A mixture of1-(2,4-dimethoxybenzyl)-3-amino-7-fluoro-5-methoxyquinoxalin-2(1H)-onefrom step (e) above (3.0 g, 8.34 mmol), anisole (4 mL, Aldrich) andtrifluoroacetic acid (60 mL, Aldrich) was heated to 65° C. for 16 h, andto 85° C. for 5 h. The reaction mixture was allowed to cool to roomtemperature and evaporated under reduced pressure. The residue waspartitioned between 25% i-PrOH/CHCl₃ and sat aq. NaHCO₃. The organiclayer was collected and evaporated to give a solid residue. The aqueouslayer was filtered and the filter cake was washed with H₂O, and driedunder vacuo. The filter cake was combined with the solid residue andrecrystallized from MeOH to give the title compound. MS (ESI, pos. ion.)m/z: 210 (M+1).

(g) 3-Amino-7-fluoro-5-hydroxyquinoxalin-2(1H)-one hydrobromide.3-Amino-7-fluoro-5-methoxyquinoxalin-2(1H)-one from step (f) above (2.0g, 9.56 mmol) was reacted with BBr₃ (1.0 M solution in CH₂Cl₂, 58 mL, 58mmol) under the conditions of Example 56 (b) to give the title compound.MS (ESI, pos. ion.) m/z: 196 (M+1).

(h) 3-Amino-5-(6-chloropyrimidin-4-yloxy)-7-fluoroquinoxalin-2(1H)-one.3-Amino-7-fluoro-5-hydroxyquinoxalin-2(1H)-one hydrobromide from step(g) above (390 mg, 2.0 mmol) was reacted with 4,6-dichloropyrimidine(298 mg, 2.0 mmol, Lancaster) under the conditions of Example 26(a) togive the title compound. MS (ESI, pos. ion.) m/z: 308 (M+1).

(i)(R)-3-Amino-7-fluoro-5-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.3-Amino-5-(6-chloropyrimidin-4-yloxy)-7-fluoroquinoxalin-2(1H)-one fromstep (h) above (200 mg, 0.65 mmol) was reacted with(R^(a))-1-(1-(4-fluorophenyl)ethyl)piperazine, Example 23(c), (135 mg,0.65 mmol) under the conditions of Example 26(b) to give the titlecompound. MS (ESI, pos. ion.) m/z: 480 (M+1). Mp: 315° C.

Example 58

(S)-3-Amino-7-fluoro-5-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one.3-Amino-5-(6-chloropyrimidin-4-yloxy)-7-fluoroquinoxalin-2(1H)-one,Example 57(h), (150 mg, 0.49 mmol) was reacted with(S)-1-(1-(4-fluorophenyl)ethyl)piperazine (101 mg, 0.49 mmol, preparedas described in Example 27) under the conditions of Example 26(b) togive the title compound. MS (ESI, pos. ion.) m/z: 480 (M+1). Mp: 288° C.

Example 59

(a) 1-((3-Fluoro-2-nitrophenoxy)methyl)-4-methoxybenzene. To asuspension of NaH (60% dispersion in mineral oil, 4.0 g, 100 mmol) inTHF (200 mL) was added dropwise 4-methoxybenzyl alcohol (12 mL, 96.2mmol) with stirring at 0° C. The mixture was stirred at room temperaturefor 15 min and 2,6-difluoronitrobenzene (15.26 g, 100 mmol, Aldrich) wasthen added. The resulting red solution was heated to 65° C. withstirring and the progress of the reaction was monitored by TLC. Thereaction mixture was cooled to room temperature and the solvent wasremoved in vacuo. The residue was dissolved in MeOH, evaporated ontoSiO₂ and eluted through a SiO₂ plug with 25% EtOAc/hexane. Evaporationof the solvent under reduced pressure gave the crude product as a yellowamorphous solid, which was used in the next step without additionalpurification. MS (ESI, neg. ion.) m/z: 274.1 [M−1].

(b) 3-(4-Methoxybenzyloxy)-N-methyl-2-nitrobenzenamine. A mixture of1-((3-fluoro-2-nitrophenoxy)methyl)₄-methoxybenzene from step (a) above(0.60 g, 2.16 mmol) and methylamine (2.0 M solution in MeOH, 3.3 mL, 6.6mmol, Aldrich) was heated in a microwave synthesizer at 140° C. for 30min. The reaction mixture was cooled to room temperature and evaporatedunder reduced pressure. The residue was dried in vacuo to give the titlecompound. MS (ESI, pos. ion.) m/z: 289 (M+1).

(c) 2-Amino-3-(methylamino)phenol. A mixture of3-(4-methoxybenzyloxy)-N-methyl-2-nitrobenzenamine from step (b) above(3.11 g, 10.8 mmol) and 10% palladium on carbon (0.31 g, Aldrich) inMeOH (50 mL) was stirred under H₂ atmosphere for 16 h. The mixture wasfiltered through a Celite® pad and the filtrate was evaporated underreduced pressure to give the title compound.

(d) 3-Amino-5-hydroxy-1-methylquinoxalin-2(1H)-one.2-Amino-3-(methylamino)phenol from step (c) above (934 mg, 6.67 mmol)was reacted with ethyl 2-ethoxy-2-iminoacetate (1.96 g, 13.52 mmol,prepared according to J. Chem. Soc. Perkin. Trans. 1, 1999, 1789) underthe conditions of Example 57(e) to give the title compound. MS (ESI,pos. ion.) m/z: 192 (M+1).

(e) 3-Amino-5-(6-chloropyrimidin-4-yloxy)-1-methylquinoxalin-2(1H)-one.3-Amino-5-hydroxy-1-methylquinoxalin-2(1H)-one from step (d) above (191mg, 1.0 mmol) was reacted with 4,6-dichloropyrimidine (149 mg, 1.0 mmol,Aldrich) under the conditions of Example 26(a) to give the titlecompound. MS (ESI, pos. ion.) m/z: 304 (M+1).

(f)(R)-3-Amino-5-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-1-methylquinoxalin-2(1H)-one.3-Amino-5-(6-chloropyrimidin-4-yloxy)-1-methylquinoxalin-2(1H)-one fromstep (e) above (100 mg, 0.33 mmol) was reacted with(R)-1-(1-(4-fluorophenyl)ethyl)piperazine, Example 23(c), (68 mg, 0.33mmol) under the conditions of Example 26(b) to give the title compound.MS (ESI, pos. ion.) m/z: 476 (M+1). Mp: 256° C.

Example 60

(S)-3-Amino-5-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-1-methylquinoxalin-2(1H)-one.3-Amino-5-(6-chloropyrimidin-4-yloxy)-1-methylquinoxalin-2(1H)-one,Example 59(e), (80 mg, 0.26 mmol) was reacted with(S)-1-(1-(4-fluorophenyl)ethyl)piperazine (55 mg, 0.26 mmol, prepared asdescribed in Example 27) under the conditions of Example 26(b) to givethe title compound. MS (ESI, pos. ion.) m/z: 476 (M+1).

Example 61

(a) 5-(6-Fluoropyrimidin-4-yloxy)quinolin-2(1H)-one. A mixture of5-hydroxyquinolin-2-(1H)-one (0.05 g, 0.31 mmol, prepared as describedin Shono, T., Matsumura, Y., Kashimura, S., J. Org. Chem. 1981, 46,3719.), 4,6-difluoropyrimidine (0.036 mL, 0.31 mmol, ABCR) and cesiumcarbonate (0.2 g, 0.62 mmol) in DMF (5 mL) was stirred at 25° C. for 2h. The reaction mixture was then diluted with H₂O (25 mL). The resultingoff-white precipitate was collected by filtration and dried under vacuoto give the title compound. MS (ESI, pos. ion.) m/z: 258 (M+1).

(b)5-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinoline-2(1H)-one.5-(6-Fluoropyrimidin-4-yloxy)quinolin-2(1H)-one from step (a) above(0.05 g, 0.19 mmol) was reacted with1-[(1S,1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine, Example 2(b), (0.04 g,0.19 mmol) under the conditions of Example 26(b) to give the titlecompound. Mp: 242.2° C. MS (ESI, pos. ion.) m/z: 446 (M+1).

ADDITIONAL EXAMPLES

The following examples were prepared from various hydroxy-substitutedbicyclic heterocycles (prepared as described in WO 2004/014871),4,6-difluoropyrimidine (ABCR) and1-[(1S,1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine (Example 2(b))according to the general procedure described for the preparation ofExample 61, or with slight modifications thereof: Melt. Point M.S. (ESI)Ex. Structure (° C.) m/z 62

148 464 (M + 1) 63

217 435 (M + 1) 64

67.2 431 (M + 1) 65

228 446 (M + 1)

Example 66

N-(4-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]oxazol-2-yl)acetamide.4-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]oxazol-2-amine(0.06 g, 0.14 mmol, Example 63) was reacted with acetic anhydride underthe conditions of Example 1(b) to give the desired product. Mp: 199.8°C. MS (ESI, pos. ion) m/z: 477 (M+1).

Example 67

(a) N-(4-(6-Fluoropyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide. Amixture of N-(4-hydroxybenzo[d]thiazol-2-yl)acetamide (0.3 g, 1.4 mmol,prepared according to the procedure described in WO 2003/099284) and4,6-difluoropyrimidine (0.17 mL, 1.4 mmol, ABCR) in DMF (3 mL) wasstirred at 25° C. for 18 h. The reaction mixture was diluted with H₂O(20 mL) and the resulting off-white precipitate was collected byfiltration, and dried under vacuo to give the title compound. MS (ESI,pos. ion) m/z: 305 (M+1).

(b) (3R)-1-(1-(4-Fluorophenyl)ethyl)-3-methylpiperazine. The titlecompound was prepared from (S)-(+)-methylpiperazine (0.5 g, 5.0 mmol,Aldrich) in a manner analogous to Example 2(a) and isolated as anamorphous solid. MS (ESI, pos. ion) m/z: 223 (M+1).

(c)N-(4-(6-((R)-4((R)-(1-(4-Fluorophenyl)ethyl)-2-methylpiperazin-1-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide.A mixture of (3R)-1-(1-(4-fluorophenyl)ethyl)-3-methylpiperazine fromstep (b) above (0.20 g, 0.90 mmol) andN-(4-(6-fluoropyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide from step(a) above (0.27 g, 0.90 mmol, Albany Molecular) in DMF (5 mL) wasstirred at 100° C. for 3 h. The reaction mixture was allowed to reach25° C. and was diluted with H₂O (40 mL). The resulting pale-orangeprecipitate was collected by filtration and dissolved in DCM (50 mL).The solution was washed with H₂O (2×), dried over anhydrous sodiumsulfate, filtered, and evaporated. The residue was purified by silicagel column chromatography (gradient: 04% MeOH/DCM) to give the productas a mixture of diastereoisomers. MS (ESI, pos. ion) m/z: 507 (M+1). Thediastereoisomers were separated by supercritical fluid chromatography[35% EtOH (0.2% diethyl amine)]. The first fraction was collected andconcentrated in vacuo to yield the title compound as a white solid. MS(ESI, pos. ion) m/z: 507 (M+1).

Example 68

N-(4-(6-((R)-4-((S)-1-(4-Fluorophenyl)ethyl)-2-methylpiperazin-1-yl)pyrimidin-4-yloxy)benzol[d]thiazol-2-yl)acetamide.This compound was isolated as a white solid from the second fraction ofthe supercritical fluid chromatography (35% EtOH (0.2% diethyl amine))separation of the diastereomeric mixture of Example 67(c). MS (ESI, pos.ion) m/z: 507 (M+1).

Example 69

(R)-N-(8-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinolin-2-yl)acetamide.8-(6-{4-[(1R)-(4-Fluoro-phenyl)-ethyl]-piperazine-1-yl}-pyrimidin-4-yloxy)-quinolin-2-ylamine,Example 23(d), (0.05 g, 0.11 mmol,) was reacted with acetic anhydrideunder the conditions of Example 1(b) to give the title compound. Mp:134° C. MS (ESI, pos. ion) m/z: 487 (M+1).

Example 70

8-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)isoquinoline.A mixture of4-fluoro-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine,Example 33(a), (0.05 g, 0.17 mmol), isoquinolin-8-ol (0.037 g, 0.25mmol, Monomer Chem, Inc.) cesium carbonate (0.081 g, 0.25 mmol), andDMSO (1 mL) was heated in a microwave synthesizer at 115° C. for 0.5 h.The reaction mixture was allowed to cool to room temperature, dilutedwith H₂O (30 mL) and extracted with DCM (2×50 mL). The combined organicextracts were washed with H₂O (2×30 mL), dried over Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silica gel columnchromatography (gradient: 0-8% MeOH/DCM) to give the title compound as awhite solid. Mp: 114° C. MS (ESI, pos. ion) m/z: 430 (M+1).

Example 71

(a) 5-Hydroxyquinoxalin-2(1H)-one. 5-Methoxy-1H-quinoxalin-2-one,Example 54(b), (0.3 g, 1.7 mmol) was reacted with AlCl₃ (2.0 g, 15.5mmol, Aldrich) under the conditions of Example 25(d) to give the titlecompound as a brown powder. MS (ESI, pos. ion) m/z: 163 (M+1).

(b)5-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinolin-2(1H)-one.4-Fluoro-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine,Example 33(a), (0.4 g, 1.3 mmol) was reacted with5-hydroxyquinolin-2(1H)-one from step (a) above (0.24 g, 1.5 mmol) underthe conditions of Example 70 to give 0.121 g (21%) of the title compoundas a pale-yellow solid. Mp: 263° C. MS (ESI, pos. ion) m/z: 447 (M+1).

(c)5-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-3,4-dihydroquinoxalin-2-(1H)-one.A mixture of5-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)quinolin-2(1H)-onefrom step (b) above (0.04 g, 0.09 mmol) and NaBH₄ (0.014 g, 0.36 mmol,Aldrich) in EtOH (2 mL) was stirred at 25° C. for 19 h. The reactionmixture was diluted with saturated sodium bicarbonate (25 mL) andextracted with DCM (3×25 mL). The combined organic extracts were washedwith H₂O (25 mL), dried over Na₂SO₄, filtered, and evaporated in vacuo.The residue was suspended in MeOH and filtered. The filter cake wasseparated and dried under vacuo to give the title compound as anoff-white solid. Mp: 221° C. MS (ESI, pos. ion) m/z: 449 (M+1).

Example 72

5-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)isoquinolin-1(2H)-one.4-Fluoro-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine,Example 33(a), (0.074 g, 0.24 mmol) was reacted with1,5-isoquinolinediol (0.058 g, 0.36 mmol, Sigma) under the conditions ofExample 70 to give the title compound. Mp: 249° C. MS (ESI, pos. ion)m/z: 446 (M+1).

Example 73

4-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzol[d]thiazol-2-amine.4-Fluoro-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine (0.145g, 0.48 mmol, Example 37(a)) was reacted with 2-amino-benzothiazol-4-ol(0.13 g, 0.78 mmol, CarboGen) under the conditions of Example 26(b) togive the title compound as a white solid. Mp: 222° C. MS (ESI, pos. ion)m/z: 451 (M+1).

Example 74

(a) 5-(6-Fluoropyrimidin-4-yloxy)-3,4-dihydroquinolin-2(1H)-one. Thetitle compound was prepared from 5-hydroxy-3,4-dihydroquinolin-2(1H)-one(0.1 g, 0.61 mmol, prepared as described in Shono, T., Matsumura, Y.,Kashimura, S., J. Org. Chem. 1981, 46, 3719.) and 4,6-difluoropyrimidine(0.072 mL, 0.62 mmol) under the conditions of Example 61(b) to give thetitle compound. MS (ESI, pos. ion) m/z: 260 (M+1).

(b)5-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)-3,4-dihydroquinolin-2(1H)-one.5-(6-Fluoropyrimidin-4-yloxy)-3,4-dihydroquinolin-2(1H)-one from step(a) above (0.075 g, 0.29 mmol) was reacted with1-[(1S,1R)-1-(4-fluoro-phenyl)-ethyl]-piperazine, Example 2(b), (0.04 g,0.19 mmol) under the conditions of Example 26(b) to give the titlecompound. MS (ESI, pos. ion) m/z: 448 (M+1).

Capsaicin-Induced Ca2+ Influx in Primary Dorsal Root Ganglion Neurons

Embryonic 19 day old (E19) dorsal root ganglia (DRG) were dissected fromtimed-pregnant, terminally anesthetized Sprague-Dawley rats (CharlesRiver, Wilmington, Mass.) and collected in ice-cold L-15 media (LifeTechnologies, Grand Island, N.Y.) containing 5% heat inactivated horseserum (Life Technologies). The DRG were then dissociated into singlecell suspension using a papain dissociation system (WorthingtonBiochemical Corp., Freehold, N.J.). The dissociated cells were pelletedat 200×g for 5 min and re-suspended in EBSS containing 1 mg/ml ovomucoidinhibitor, 1 mg/ml ovalbumin and 0.005% DNase. Cell suspension wascentrifuged through a gradient solution containing 10 mg/ml ovomucoidinhibitor, 10 mg/ml ovalbumin at 200×g for 6 min to remove cell debris;and filtered through a 88-μm nylon mesh (Fisher Scientific, Pittsburgh,Pa.) to remove any clumps. Cell number was determined with ahemocytometer and cells were seeded into poly-ornithine 100 μg/ml(Sigma) and mouse laminin 1 μg/ml (Life Technologies)-coated 96-wellplates at 10×10³ cells/well in complete medium. The complete mediumconsists of minimal essential medium (MEM) and Ham's F12, 1:1,penicillin (100 U/ml), and streptomycin (100 μg/ml), and nerve growthfactor (10 ng/ml), 10% heat inactivated horse serum (Life Technologies).The cultures were kept at 37° C., 5% CO₂ and 100% humidity. Forcontrolling the growth of non-neuronal cells, 5-fluoro-2′-deoxyuridine(75 μM) and uridine (180 μM) were included in the medium. Activation ofVR1 is achieved in these cellular assays using either a capsaicinstimulus (ranging from 0.01-10 μM) or by an acid stimulus (addition of30 mM Hepes/Mes buffered at pH 4.1). Compounds are also tested in anassay format to evaluate their agonist properties at VR1.

Capsaicin Antagonist Assay: E-19 DRG cells at 5 days in culture areincubated with serial concentrations of VR1 antagonists, in HBSS (Hanksbuffered saline solution supplemented with BSA 0.1 mg/ml and 1 mM Hepesat pH 7.4) for 15 min, 37° C. Cells are then challenged with a VR1agonist, capsaicin 200 nM, in activation buffer containing 0.1 mg/mlBSA, 15 mM Hepes, pH 7.4, and 10 μCi/Ml ⁴⁵Ca²⁺ (Amersham) in Ham's F12for 2 min at 37° C.

Acid Antagonist Assay: Compounds are pre-incubated with E-19 DRG cellsfor 2 minutes prior to addition of Calcium-45 in 30 mM Hepes/Mes buffer(Final Assay pH 5) and then left for an additional 2 minutes prior tocompound washout. Final 45Ca (Amersham CES3-2mCi) at 10 μCi/mL.

Agonist Assay: Compounds are incubated with E-19 DRG cells for 2 minutesin the presence of Calcium-45 prior to compound washout. Final ⁴⁵Ca²⁺(Amersham CES3-2 mCi) at 10 μCi/mL.

Compound Washout and Analysis: Assay plates are washed using an ELX405plate washer (Bio-Tek Instruments Inc.) immediately after functionalassay. Wash 3× with PBS Mg2+/Ca2+ free, 0.1 mg/mL BSA. Aspirate betweenwashes. Read plates using a MicroBeta Jet (Wallac Inc.). Compoundactivity is then calculated using appropriate computational algorithms.

⁴⁵Calcium²⁺ Assay Protocol

Compounds may be assayed using Chinese Hamster Ovary cell lines stablyexpressing either human VR1 or rat VR1 under a CMV promoter. Cells canbe cultured in Growth Medium, routinely passaged at 70% confluency usingtrypsin and plated in the assay plate 24 hours prior to compoundevaluation.

Possible Growth Medium:

-   -   DMEM, high glucose (Gibco 11965-084).    -   10% Dialyzed serum (Hyclone SH30079.03).    -   1× Non-Essential Amino Acids (Gibco 11140-050).    -   1× Glutamine-Pen-Strep (Gibco 10378-016).    -   Geneticin, 450 μg/mL (Gibco 10131-035).        Compounds can be diluted in 100% DMSO and tested for activity        over several log units of concentration [40 μM-2 pM]. Compounds        may be further diluted in HBSS buffer (pH 7.4) 0.1 mg/mL BSA,        prior to evaluation. Final DMSO concentration in assay would be        0.5%. Each assay plate can be controlled with a buffer only and        a known antagonist compound (either capsazepine or one of the        described VR1 antagonists).

Activation of VR1 can be achieved in these cellular assays using eithera capsaicin stimulus (ranging from 0.1-1 μM) or by an acid stimulus(addition of 30 mM Hepes/Mes buffered at pH 4.1). Compounds may alsotested in an assay format to evaluate their agonist properties at VR1.

Capsaicin Antagonist Assay: Compounds may be pre-incubated with cells(expressing either human or rat VR1) for 2 minutes prior to addition ofCalcium-45 and Capsaicin and then left for an additional 2 minutes priorto compound washout. Capsaicin (0.5 nM) can be added in HAM's F12, 0.1mg/mL BSA, 15 mM Hepes at pH 7.4. Final ⁴⁵Ca (Amersham CES3-2mCi) at 10μCi/mL.

The following compounds exhibit IC50 values of less than 10 mM in theHuman VR1 Capsaicin Antagonist Assay:

-   2-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;-   2-chloro-8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;-   3-((6-(4-((11S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)isoquinoline;-   3-amino-5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;-   3-amino-5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1-methyl-2(1H)-quinoxalinone;-   3-amino-5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1-methyl-2(1H)-quinoxalinone;-   3-amino-5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;-   3-amino-5-((6-(4-((11S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1-methyl-2(1H)-quinoxalinone;-   3-amino-5-((6-(4-((1S,1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;-   3-amino-7-fluoro-5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;-   3-amino-7-fluoro-5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;-   3-amino-7-fluoro-5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;-   4-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;-   4-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)isoquinoline;-   4-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-amine;-   4-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-dihydro-2H-benzimidazol-2-one;-   4-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-methyl-1H-benzimidazole;-   4-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1H-indole;-   4-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzoxazol-2-amine;-   4-(2,3-dihydro-1,4-benzodioxin-6-yloxy)-6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)pyrimidine;-   4-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-6-{4-[1-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-pyrimidine;-   5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,4-dihydro-2,3-quinoxalinedione;-   5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)isoquinoline;-   5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;-   5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinolinone;-   5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-3,4-dihydro-2(1H)-quinolinone;-   5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-dihydro-2H-benzimidazol-2-one;-   5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;-   5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;-   5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-3,4-dihydro-2(1H)-quinoxalinone;-   5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-4a,8a-dihydroquinoxaline;    5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1    (2H)-isoquinolinone;-   6-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1H-indole;-   6-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2H-1,4-benzoxazin-3(4H)-one;-   6-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)isoquinoline;-   6-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-3,4-dihydro-2H-1,4-benzoxazine;-   7-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1H-indole;-   7-((6-(4-((11S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;-   7-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)isoquinoline;-   7-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-quinolinol;-   8-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-quinolinamine;-   8-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-quinoxalinamine;-   8-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;-   8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-quinolinamine;-   8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)imidazo[1,2-a]pyridine;-   8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,4-dihydro-3(2H)-isoquinolinone;-   8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-quinoxalinamine;-   8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)isoquinoline;-   N-(4-((6-((2R)-4-((1R)-1-(4-fluorophenyl)ethyl)-2-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-((2R)-4-((1S)-1-(4-fluorophenyl)ethyl)-2-methyl-1-piperazinyl)4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-((2R)-4-((1S)-1-(4-fluorophenyl)ethyl)-2-methyl-1-piperazinyl)4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-((2S)-4-((1S,1R)-1-(4-fluorophenyl)ethyl)-2-methyl-1-piperazinyl)4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-((3R)-4-((1R)-1-(4-fluorophenyl)ethyl)-3-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-((3R)-4-((1R)-1-(4-fluorophenyl)propyl)-3-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-((3R)-4-((1S)-1-(4-fluorophenyl)ethyl)-3-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-((3R)-4-((1S)-1-(4-fluorophenyl)propyl)-3-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzoxazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(2,4-difluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(2-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(2-furanyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(2-thienyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(3-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(3-thienyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(4-(methyloxy)phenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(4-bromophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(4-chlorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(4-fluorophenyl)propyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(4-pyridinyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(5-bromo-2-thienyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;-   N-(4-((6-(4-((1S,1R)-1-(5-chloro-2-thienyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;    and-   N-(8-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-quinolinyl)acetamide.

Acid Antagonist Assay: Compounds can be pre-incubated with cells(expressing either human or rat VR1) for 2 minutes prior to addition ofCalcium-45 in 30 mM Hepes/Mes buffer (Final Assay pH 5) and then leftfor an additional 2 minutes prior to compound washout. Final ⁴⁵Ca(Amersham CES3-2mCi) at 10 μCi/mL.

Agonist Assay: Compounds can be incubated with cells (expressing eitherhuman or rat VR1) for 2 minutes in the presence of Calcium-45 prior tocompound washout. Final ⁴⁵Ca (Amersham CES3-2mCi) at 10 μCi/mL.

Compound Washout and Analysis: Assay plates can be washed using anELX405 plate washer (Bio-Tek Instruments Inc.) immediately afterfunctional assay. One can wash 3× with PBS Mg2⁺/Ca²⁺ free, 0.1 mg/mLBSA, aspirating between washes. Plates may be read using a MicroBeta Jet(Wallac Inc.). Compound activity may then calculated using appropriatecomputational algorithms.

Useful nucleic acid sequences and proteins may be found in U.S. Pat.Nos. 6,335,180, 6, 406,908 and 6,239,267, herein incorporated byreference in their entirety.

For the treatment of vanilloid-receptor-diseases, such as acute,inflammatory and neuropathic pain, dental pain, general headache,migraine, cluster headache, mixed-vascular and non-vascular syndromes,tension headache, general inflammation, arthritis, rheumatic diseases,osteoarthritis, inflammatory bowel disorders, inflammatory eyedisorders, inflammatory or unstable bladder disorders, psoriasis, skincomplaints with inflammatory components, chronic inflammatoryconditions, inflammatory pain and associated hyperalgesia and allodynia,neuropathic pain and associated hyperalgesia and allodynia, diabeticneuropathy pain, causalgia, sympathetically maintained pain,deafferentation syndromes, asthma, epithelial tissue damage ordysfunction, herpes simplex, disturbances of visceral motility atrespiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, the compounds of the present invention may be administeredorally, parentally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants, and vehicles. The term parenteral asused herein includes, subcutaneous, intravenous, intramuscular,intrasternal, infusion techniques or intraperitoneally.

Treatment of diseases and disorders herein is intended to also includethe prophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) believed to be in need of preventative treatment, such as, forexample, pain, inflammation and the like.

The dosage regimen for treating vanilloid-receptor-mediated diseases,cancer, and/or hyperglycemia with the compounds of this invention and/orcompositions of this invention is based on a variety of factors,including the type of disease, the age, weight, sex, medical conditionof the patient, the severity of the condition, the route ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. Dosage levels of the order from about 0.01 mg to 30 mg perkilogram of body weight per day, preferably from about 0.1 mg to 10mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for allmethods of use disclosed herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, acacia, gelatin, sodium alginate,polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, e.g., by formationof diastereoisomeric salts, by treatment with an optically active acidor base. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

Likewise, the compounds of this invention may exist as isomers, that iscompounds of the same molecular formula but in which the atoms, relativeto one another, are arranged differently. In particular, the alkylenesubstituents of the compounds of this invention, are normally andpreferably arranged and inserted into the molecules as indicated in thedefinitions for each of these groups, being read from left to right.However, in certain cases, one skilled in the art will appreciate thatit is possible to prepare compounds of this invention in which thesesubstituents are reversed in orientation relative to the other atoms inthe molecule. That is, the substituent to be inserted may be the same asthat noted above except that it is inserted into the molecule in thereverse orientation. One skilled in the art will appreciate that theseisomeric forms of the compounds of this invention are to be construed asencompassed within the scope of the present invention.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. The salts include, but are notlimited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Also encompassed in the scope of the present invention arepharmaceutically acceptable esters of a carboxylic acid or hydroxylcontaining group, including a metabolically labile ester or a prodrugform of a compound of this invention. A metabolically labile ester isone which may produce, for example, an increase in blood levels andprolong the efficacy of the corresponding non-esterified form of thecompound. A prodrug form is one which is not in an active form of themolecule as administered but which becomes therapeutically active aftersome in vivo activity or biotransformation, such as metabolism, forexample, enzymatic or hydrolytic cleavage. For a general discussion ofprodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use. Esters of acompound of this invention, may include, for example, the methyl, ethyl,propyl, and butyl esters, as well as other suitable esters formedbetween an acidic moiety and a hydroxyl containing moiety. Metabolicallylabile esters, may include, for example, methoxymethyl, ethoxymethyl,iso-propoxymethyl, α-methoxyethyl, groups such asα-((C₁-C₄)alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl,propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethylgroups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C₁-C₃alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl,isopropylthiomethyl, etc.; acyloxymethyl groups, for example,pivaloyloxymethyl, α-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; orα-acyloxy-α-substituted methyl groups, for example α-acetoxyethyl.

Further, the compounds of the invention may exist as crystalline solidswhich can be crystallized from common solvents such as ethanol,N,N-dimethyl-formamide, water, or the like. Thus, crystalline forms ofthe compounds of the invention may exist as polymorphs, solvates and/orhydrates of the parent compounds or their pharmaceutically acceptablesalts. All of such forms likewise are to be construed as falling withinthe scope of the invention.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound having the structure:

or any pharmaceutically-acceptable salt or hydrate thereof, wherein: Xis N or C; wherein, when X is N,

represents single bond, and when X is C, then

represents a single or double bond; R¹ is a saturated, partiallysaturated or unsaturated 5-, 6- or 7-membered ring containing 1, 2, 3 or4 atoms selected from N, O and S, wherein the carbon atoms of the ringare substituted by 0, 1 or 2 oxo groups and the ring is substituted by0, 1, 2 or 3 substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo,cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —C(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a); or R¹ is phenyl substituted by 1, 2 or 3substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro,—C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); R² isindependently a partially saturated or unsaturated 8-, 9-, 10- or11-membered bicyclic ring containing 1, 2, 3 or 4 atoms selected from N,O and S, wherein the carbon atoms of the ring are substituted by 0, 1 or2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² is independently apartially saturated or unsaturated 9-, 10- or 11-membered bicycliccarbocyclic ring substituted by 1, 2 or 3 substituents selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); R³ and R^(3′) areindependently, at each instance, H, methyl or ethyl; or R³ and R^(3′)together may be combined with the carbon atom to which they are attachedto form cyclopropyl; R⁴ is H or methyl; R^(a) is independently, at eachinstance, H or R^(b); and R^(b) is independently, at each instance,phenyl, benzyl or C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl beingsubstituted by 0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.2. A compound according to claim 1, or any pharmaceutically-acceptablesalt or hydrate thereof, having the structure

or any pharmaceutically-acceptable salt thereof, wherein: R² isindependently a partially saturated or unsaturated 8-, 9-, 10- or11-membered bicyclic ring containing 1, 2, 3 or 4 atoms selected from N,O and S, wherein the carbon atoms of the ring are substituted by 0, 1 or2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); or R² is independently apartially saturated or unsaturated 9-, 10- or 11-membered bicycliccarbocyclic ring substituted by 1, 2 or 3 substituents selected fromC₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR, —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)Rb —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); R⁴ is H ormethyl; R⁵ is independently in each instance selected from H, C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); R^(a) is independently, ateach instance, H or R^(b); and R^(b) is independently, at each instance,phenyl, benzyl or C₁₋₆alkyl, the phenyl, benzyl and C₁₋₆alkyl beingsubstituted by 0, 1, 2 or 3 substituents selected from halo, C₁₋₄alkyl,C₁₋₃haloalkyl, —OC₁₋₄alkyl, —NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.3. A compound according to claim 1, or any pharmaceutically-acceptablesalt or hydrate thereof, having the structure:

or any pharmaceutically-acceptable salt thereof, wherein: R² isindependently a partially saturated or unsaturated 8-, 9-, 10- or11-membered bicyclic ring containing 1, 2, 3 or 4 atoms selected from N,O and S, wherein the carbon atoms of the ring are substituted by 0, 1 or2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituentsselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a); R⁴ is H ormethyl; R^(a) is independently, at each instance, H or R^(b); and R^(b)is independently, at each instance, phenyl, benzyl or C₁₋₆alkyl, thephenyl, benzyl and C₁₋₆alkyl being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alkyl, C₁₋₃haloalkyl, —OC₁₋₄alkyl,—NH₂, —NHC₁₋₄alkyl, —N(C₁₋₄alkyl)C₁₋₄alkyl.
 4. A compound according toclaim 1, or any pharmaceutically-acceptable salt or hydrate thereof,wherein R¹ is a saturated, partially saturated or unsaturated 5-, 6- or7-membered ring containing 1, 2, 3 or 4 atoms selected from N, O and S,wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxogroups and the ring is substituted by 0, 1, 2 or 3 substituents selectedfrom C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).
 5. A compoundaccording to claim 1, or any pharmaceutically-acceptable salt or hydratethereof, wherein R¹ is pyridinyl, furanyl, thiophenyl or pyrimidinyl,any of which is substituted by 0, 1, 2 or 3 substituents selected fromC₁₋₈alkyl, C₁₋₄haloalkyl and halo.
 6. A compound according to claim 1,or any pharmaceutically-acceptable salt or hydrate thereof, wherein R¹is phenyl substituted by 1, 2 or 3 substituents selected from C₁₋₈alkyl,C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a),—OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).
 7. A compoundaccording to claim 1, or any pharmaceutically-acceptable salt or hydratethereof, wherein R¹ is phenyl substituted by 1, 2 or 3 substituentsselected from C₁₋₈alkyl, C₁₋₄haloalkyl, halo and —OR^(a);
 8. A compoundaccording to claim 1, or any pharmaceutically-acceptable salt or hydratethereof, wherein R² is independently a partially saturated orunsaturated 8-, 9-, 10- or 11-membered bicyclic ring containing 1, 2, 3or 4 atoms selected from N, O and S, wherein the carbon atoms of thering are substituted by 0, 1 or 2 oxo groups and the ring is substitutedby 0, 1, 2 or 3 substituents selected from C₁₋₈alkyl, C₁₋₄haloalkyl,halo, cyano, nitro, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OR^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC(═O)N(R^(a))S(═O)₂R^(b), —OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a),—S(═O)₂N(R^(a))C(═O)R^(b), —S(═O)₂N(R^(a))C(═O)OR^(b),—S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and—NR^(a)C₂₋₆alkylOR^(a).
 9. A compound according to claim 1, or anypharmaceutically-acceptable salt or hydrate thereof, wherein R² isquinolin-8-yl, benzoxazol-4-yl, benzothiazol-4-yl or quinoxalinon-5-yl,either of which is substituted by 0, 1, 2 or 3 substituents selectedfrom C₁₋₈alkyl, C₁₋₄haloalkyl, halo, cyano, nitro, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OR^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC(═O)N(R^(a))S(═O)₂R^(b),—OC₂₋₆alkylNR^(a)R^(a), —OC₂₋₆alkylOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —S(═O)₂N(R^(a))C(═O)R^(b),—S(═O)₂N(R^(a))C(═O)OR^(b), —S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkylNR^(a)R^(a) and —NR^(a)C₂₋₆alkylOR^(a).
 10. A compound according toclaim 1, or any pharmaceutically-acceptable salt or hydrate thereof,wherein R³ is H and R^(3′) is methyl.
 11. A compound selected from thegroup of:2-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;2-chloro-8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;3-((6-(4-((11S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)isoquinoline;3-amino-5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;3-amino-5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1-methyl-2(1H)-quinoxalinone;3-amino-5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1-methyl-2(1H)-quinoxalinone;3-amino-5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;3-amino-5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1-methyl-2(1H)-quinoxalinone;3-amino-5-((6-(4-((1S,1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;3-amino-7-fluoro-5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;3-amino-7-fluoro-5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;3-amino-7-fluoro-5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;4-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;4-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)isoquinoline;4-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-amine;4-((6-(4-((11S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-dihydro-2H-benzimidazol-2-one;4-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-methyl-1H-benzimidazole;4-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1H-indole;4-((6-(4-((11S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzoxazol-2-amine;4-(2,3-dihydro-1,4-benzodioxin-6-yloxy)-6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)pyrimidine;4-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-6-{4-[1-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-pyrimidine;5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,4-dihydro-2,3-quinoxalinedione;5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)isoquinoline;5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-3,4-dihydro-1(2H)-isoquinolinone;5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinolinone;5-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-3,4-dihydro-2(1H)-quinolinone;5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-dihydro-2H-benzimidazol-2-one;5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-amine;5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2(1H)-quinoxalinone;5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-3,4-dihydro-2(1H)-quinoxalinone;5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-4a,8a-dihydroquinoxaline;5-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1(2H)-isoquinolinone;6-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1H-indole;6-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2H-1,4-benzoxazin-3(4H)-one;6-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)isoquinoline;6-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-3,4-dihydro-2H-1,4-benzoxazine;6-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;7-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1H-indole;7-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;7-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)isoquinoline;7-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-quinolinol;8-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-quinolinamine;8-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-quinoxalinamine;8-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)quinoline;8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-quinolinamine;8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)imidazo[1,2-a]pyridine;8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,4-dihydro-3(2H)-isoquinolinone;8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-quinoxalinamine;8-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)isoquinoline;N-(4-((6-((2R)-4-((1R)-1-(4-fluorophenyl)ethyl)-2-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-((2R)-4-((1S)-1-(4-fluorophenyl)ethyl)-2-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-((2R)-4-((1S)-1-(4-fluorophenyl)ethyl)-2-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-((2S)-4-((1S,1R)-1-(4-fluorophenyl)ethyl)-2-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-((3R)₄-((1R)-1-(4-fluorophenyl)ethyl)-3-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-((3R)-4-((1R)-1-(4-fluorophenyl)propyl)-3-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-((3R)-4-((1S)-1-(4-fluorophenyl)ethyl)-3-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-((3R)₄-((1S)-1-(4-fluorophenyl)propyl)-3-methyl-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzoxazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(2,4-difluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(2-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(2-furanyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(2-thienyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(3-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(3-thienyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(4-(methyloxy)phenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(4-(trifluoromethyl)phenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(4-bromophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(4-chlorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((S,1R)-1-(4-fluorophenyl)propyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(4-pyridinyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(5-bromo-2-thienyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;N-(4-((6-(4-((1S,1R)-1-(5-chloro-2-thienyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-1,3-benzothiazol-2-yl)acetamide;andN-(8-((6-(4-((1R)-1-(4-fluorophenyl)ethyl)-1-piperazinyl)-4-pyrimidinyl)oxy)-2-quinolinyl)acetamide;or any pharmaceutically-acceptable salts or hydrate thereof.
 12. Amethod of treating acute, inflammatory and neuropathic pain, dentalpain, general headache, migraine, cluster headache, mixed-vascular andnon-vascular syndromes, tension headache, general inflammation,arthritis, rheumatic diseases, osteoarthritis, inflammatory boweldisorders, depression, anxiety, inflammatory eye disorders, inflammatoryor unstable bladder disorders, psoriasis, skin complaints withinflammatory components, chronic inflammatory conditions, inflammatorypain and associated hyperalgesia and allodynia, neuropathic pain andassociated hyperalgesia and allodynia, diabetic neuropathy pain,causalgia, sympathetically maintained pain, deafferentation syndromes,asthma, epithelial tissue damage or dysfunction, herpes simplex,disturbances of visceral motility at respiratory, genitourinary,gastrointestinal or vascular regions, wounds, burns, allergic skinreactions, pruritus, vitiligo, general gastrointestinal disorders,gastric ulceration, duodenal ulcers, diarrhea, gastric lesions inducedby necrotising agents, hair growth, vasomotor or allergic rhinitis,bronchial disorders or bladder disorders, comprising the step ofadministering a compound according to claim
 1. 13. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically-acceptable diluent or carrier.